Substituted thieno[3,2-d]pyridines as inhibitors of the VEGF receptor and HGF receptor

ABSTRACT

The invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/592,913, filed on Jul. 30, 2004, and U.S.Provisional Patent Application Ser. No. 60/683,038, filed on May 20,2005, the contents of which are incorporated herein by reference intheir entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to the inhibition of VEGF receptor signaling andHGF receptor signaling. More particularly, the invention relates tocompounds and methods for the inhibition of VEGF receptor signaling andHGF receptor signaling.

2. Summary of the Related Art

Angiogenesis is an important component of certain normal physiologicalprocesses such as embryogenesis and wound healing, but aberrantangiogenesis contributes to some pathological disorders and inparticular to tumor growth.^(1,2) VEGF-A (vascular endothelial growthfactor A) is a key factor promoting neovascularization (angiogenesis) oftumors.³⁻⁷ VEGF induces endothelial cell proliferation and migration bysignaling through two high affinity receptors, the fins-like tyrosinekinase receptor, Flt-1, and the kinase insert domain-containingreceptor, KDR.^(8,9,10). These signaling responses are criticallydependent upon receptor dimerization and activation of intrinsicreceptor tyrosine kinase (RTK) activity. The binding of VEGF as adisulfide-linked homodimer stimulates receptor dimerization andactivation of the RTK domain ¹¹. The kinase activity autophosphorylatescytoplasmic receptor tyrosine residues, which then serve as bindingsites for molecules involved in the propagation of a signaling cascade.Although multiple pathways are likely to be elucidated for bothreceptors, KDR signaling is most extensively studied, with a mitogenicresponse suggested to involve ERK-1 and ERK-2 mitogen-activatedproteinkinases ¹².

Disruption of VEGF receptor signaling is a highly attractive therapeutictarget in cancer, as angiogenesis is a prerequisite for all solid tumorgrowth, and that the mature endothelium remains relatively quiescent(with the exception of the female reproductive system and woundhealing). A number of experimental approaches to inhibiting VEGFsignaling have been examined, including use of neutralizing antibodies^(13,14,15), receptor antagonists ¹⁶, soluble receptors ¹⁷, antisenseconstructs ¹⁸ and dominant-negative strategies ¹⁹.

Despite the attractiveness of anti-angiogenic therapy by VEGF inhibitionalone, several issues may limit this approach. VEGF expression levelscan themselves be elevated by numerous diverse stimuli and perhaps mostimportantly, the hypoxic state of tumors resulting from VEGFrinhibition, can lead to the induction of factors that themselves promotetumor invasion and metastasis thus, potentially undermining the impactof VEGF inhibitors as cancer therapeutics ²⁰.

The HGF (hepatocyte growth factor) and the HGF receptor, c-met, areimplicated in the ability of tumor cells to undermine the activity ofVEGF inhibition ²⁰. HGF derived from either stromal fibroblastssurrounding tumor cells or expressed from the tumor itself has beensuggested to play a critical role in tumor angiogenesis, invasion andmetastasis ^(21,22). For example, invasive growth of certain cancercells is drastically enhanced by tumor-stromal interactions involvingthe HGF/c-Met (HGF receptor) pathway ^(21,24,25). HGF, which wasoriginally identified as a potent mitogen for hepatocytes ^(26,27) isprimarily secreted from stromal cells, and the secreted HGF can promotemotility and invasion of various cancer cells that express c-Met in aparacrine manner ^(28,29,30). Binding of HGF to c-Met leads to receptorphosphorylation and activation of Ras/mitogen-activated protein kinase(MAPK) signaling pathway, thereby enhancing malignant behaviors ofcancer cells ^(30,31). Moreover, stimulation of the HGF/c-met pathwayitself can lead to the induction of VEGF expression, itself contributingdirectly to angiogenic activity³².

Thus, anti-tumor anti-angiogenic strategies or approaches that targetboth VEGF/VEGFr signaling and HGF/c-met signaling may circumvent theability of tumor cells to overcome VEGF inhibition alone and mayrepresent improved cancer therapeutics.

Here we describe small molecules that are potent inhibitors of both theVEGF receptor KDR and the HGF receptor c-met.

BRIEF SUMMARY OF THE INVENTION

The present invention provides new compounds and methods for treatingcell proliferative diseases. The compounds of the invention are dualfunction inhibitors, capable of inhibiting both VEGF and HGF.Accordingly, the invention provides new inhibitors of VEGF receptorsignaling and HGF receptor signaling, including the VEGF receptor KDRand the HGF receptor c-met.

In a first aspect, the invention provides compounds of formula A thatare useful as inhibitors of VEGF receptor signaling and HGF receptorsignaling.

In a second aspect, the invention provides compounds of formula B thatare useful as inhibitors of VEGF receptor signaling and HGF receptorsignaling.

In a third aspect, the invention provides compositions comprising acompound of the present invention that is an inhibitor of VEGF receptorsignaling and HGF receptor signaling, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier, excipient, ordiluent.

In a fourth aspect, the invention provides a method of simultaneouslyinhibiting VEGF receptor signaling and HGF receptor signaling in a cell,comprising contacting a cell in which inhibition of VEGF receptorsignaling and HGF receptor signaling is desired with a compound of theinvention.

The foregoing merely summarizes certain aspects of the invention and isnot intended to be limiting in nature. These aspects and other aspectsand embodiments are described more fully below.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The invention provides compounds and methods for inhibiting the VEGFreceptor KDR and the HGF receptor c-met. The invention also providescompositions and methods for treating cell proliferative diseases andconditions. The patent and scientific literature referred to hereinestablishes knowledge that is available to those with skill in the art.The issued patents, applications, and references that are cited hereinare hereby incorporated by reference to the same extent as if each wasspecifically and individually indicated to be incorporated by reference.In the case of inconsistencies, the present disclosure will prevail.

For purposes of the present invention, the following definitions will beused (unless expressly stated otherwise):

The terms “inhibitor of VEGF receptor signaling” and “inhibitor of HGFreceptor signaling” are used to identify a compound having a structureas defined herein, which is capable of interacting with a HGF receptorand a VEGF receptor and inhibiting the activity of HGF and VEGF. In somepreferred embodiments, such reduction of activity is at least about 50%,more preferably at least about 75%, and still more preferably at leastabout 90%.

For simplicity, chemical moieties are defined and referred to throughoutprimarily as univalent chemical moieties (e.g., alkyl, aryl, etc.).Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃-CH₂—), in certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂-CH₂—), which is equivalent to the term “alkylene.”(Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene.)All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maybe defined, for example, as (A)_(a)—B—, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B— and when a is I the moiety isA-B—. Also, a number of moieties disclosed herein exist in multipletautomeric forms, all of which are intended to be encompassed by anygiven tautomeric structure.

The term “hydrocarbyl” refers to a straight, branched, or cyclic alkyl,alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbyl is usedto refer to a covalent bond. Thus, “C₀-C₃-hydrocarbyl” includes acovalent bond, methyl, ethyl, ethenyl, ethynyl, propyl, propenyl,propynyl, and cyclopropyl.

The term “alkyl” as employed herein refers to straight and branchedchain aliphatic groups having from 1 to 12 carbon atoms, preferably 1-8carbon atoms, and more preferably 1-6 carbon atoms, which is optionallysubstituted with one, two or three substituents. Preferred alkyl groupsinclude, without limitation, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A “C₀” alkyl (as in“C₀-C₃-alkyl”) is a covalent bond (like “C₀” hydrocarbyl).

The term “alkenyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon doublebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkenyl groups include,without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

The term “alkynyl” as used herein means an unsaturated straight orbranched chain aliphatic group with one or more carbon-carbon triplebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl,or alkynyl group, as defined hereinabove, that is positioned between andserves to connect two other chemical groups. Preferred alkylene groupsinclude, without limitation, methylene, ethylene, propylene, andbutylene. Preferred alkenylene groups include, without limitation,ethenylene, propenylene, and butenylene. Preferred alkynylene groupsinclude, without limitation, ethynylene, propynylene, and butynylene.

The term “cycloalkyl” as employed herein includes saturated andpartially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons,preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, whereinthe cycloalkyl group additionally is optionally substituted. Preferredcycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl.

The term “heteroalkyl” refers to an alkyl group, as defined hereinabove,wherein one or more carbon atoms in the chain are replaced by aheteroatom selected from the group consisting of O, S, NH, N-alkyl, SO,SO₂, SO₂NH, or NHSO₂.

An “aryl” group is a C₆-C₁₄ aromatic moiety comprising one to threearomatic rings, which is optionally substituted. Preferably, the arylgroup is a C₆-C₁₀ aryl group. Preferred aryl groups include, withoutlimitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aralkyl”or “arylalkyl” group comprises an aryl group covalently linked to analkyl group, either of which may independently be optionally substitutedor unsubstituted. Preferably, the aralkyl group is(C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl.

A “heterocyclyl” or “heterocyclic” group is a ring structure having fromabout 3 to about 12 atoms, wherein one or more atoms are selected fromthe group consisting of N, O, S, SO, and SO₂. The heterocyclic group isoptionally substituted on carbon at one or more positions. Theheterocyclic group is also independently optionally substituted onnitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl,arylcarbonyl, arylsulfonyl, alkoxycarbonyl, or aralkoxycarbonyl.Preferred heterocyclic groups include, without limitation, epoxy,aziridinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl,thiazolidinyl, oxazolidinyl, oxazolidinonyl, and morpholino. In certainpreferred embodiments, the heterocyclic group is fused to an aryl,heteroaryl, or cycloalkyl group. Examples of such fused heterocylesinclude, without limitation, tetrahydroquinoline and dihydrobenzofuran.Specifically excluded from the scope of this term are compounds where anannular O or S atom is adjacent to another O or S atom.

As used herein, the term “heteroaryl” refers to groups having 5 to 14ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14π-electrons shared in a cyclic array; and having, in addition to carbonatoms, from one to three heteroatoms per ring selected from the groupconsisting of N, O, and S. The term “heteroaryl” is also meant toencompass monocyclic and bicyclic groups. For example, a heteroarylgroup may be pyrimidinyl, pyridinyl, benzimidazolyl, thienyl,benzothiazolyl, benzofuranyl and indolinyl. A “heteroaralkyl” or“heteroarylalkyl” group comprises a heteroaryl group covalently linkedto an alkyl group, either of which is independently optionallysubstituted or unsubstituted. Preferred heteroalkyl groups comprise aC₁-C₆ alkyl group and a heteroaryl group having 5, 6, 9, or 10 ringatoms. Specifically excluded from the scope of this term are compoundshaving adjacent annular O and/or S atoms. Examples of preferredheteroaralkyl groups include pyridylmethyl, pyridylethyl,pyrrolylmethyl, pyrrolylethyl, imidazolylmethyl, imidazolylethyl,thiazolylmethyl, and thiazolylethyl. Specifically excluded from thescope of this term are compounds having adjacent annular O and/or Satoms.

For simplicity, reference to a “C_(n)-C_(m)” heterocyclyl or heteroarylmeans a heterocyclyl or heteroaryl having from “n” to “m” annular atoms,where “n” and “m” are integers. Thus, for example, a C₅-C₆-heterocyclylis a 5- or 6-membered ring having at least one heteroatom, and includespyrrolidinyl (C₅) and piperidinyl (C₆); C₆-hetoaryl includes, forexample, pyridyl and pyrimidyl.

An “arylene,” “heteroarylene,” or “heterocyclylene” group is an aryl,heteroaryl, or heterocyclyl group, as defined hereinabove, that ispositioned between and serves to connect two other chemical groups.

Preferred heterocyclyls and heteroaryls include, but are not limited to,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, pyridotriazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, and xanthenyl.

As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl, aryl,heteroaryl, heterocyclic, urea, etc.) is described as “optionallysubstituted” it is meant that the group optionally has from one to four,preferably from one to three, more preferably one or two, non-hydrogensubstituents. Suitable substituents include, without limitation, halo,hydroxy, oxo (e.g., an annular —CH— substituted with oxo is —C(O)—)nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy,amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl,carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido,arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, andureido groups. Preferred substituents, which are themselves not furthersubstituted (unless expressly stated otherwise) are:

-   -   (a) halo, hydroxy, cyano, oxo, carboxy, formyl, nitro, amino,        amidino, guanidino,    -   (b) C₁-C₅ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,        carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl,        arylalkyl, C₁-C8 alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy, C₁-C₈        alkoxycarbonyl, aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈ acylamino,        C₁-C₈ alkylthio, arylalkylthio, arylthio, C₁-C₈ alkylsulfinyl,        arylalkylsulfinyl, arylsulfinyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, C₀-C₆ N-alkyl carbamoyl, C₂-C₁₅        N,N-dialkylcarbamoyl, C₃-C₇ cycloalkyl, aroyl, aryloxy,        arylalkyl ether, aryl, aryl fused to a cycloalkyl or heterocycle        or another aryl ring, C₃-C₇ heterocycle, C₅-C₁₄ heteroaryl, or        any of these rings fused or spiro-fused to a cycloalkyl,        heterocyclyl, or aryl, wherein each of the foregoing is further        optionally substituted with one more moieties listed in (a),        above; and    -   (c) —(CH₂)_(s)—NR³⁰R³¹, wherein s is from 0 (in which case the        nitrogen is directly bonded to the moiety that is substituted)        to 6, and R³⁰ and R³¹ are each independently hydrogen, cyano,        oxo, carboxamido, amidino, C₁-C₈ hydroxyalkyl, C₁-C₃ alkylaryl,        aryl-C₁-C₃ alkyl, C₁-C₈ alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy,        C₁-C₈ alkoxycarbonyl, aryloxycarbonyl, aryl-C₁-C₃        alkoxycarbonyl, C₂-C₈ acyl, C₁-C₈ alkylsulfonyl,        arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl,        heterocyclyl, or heteroaryl, wherein each of the foregoing is        further optionally substituted with one more moieties listed in        (a), above; or        -   R³⁰ and R³¹ taken together with the N to which they are            attached form a heterocyclyl or heteroaryl, each of which is            optionally substituted with from 1 to 3 substituents, from            (a), above.

Especially preferred substituents on alkyl groups include halogen andhydroxy.

Especially preferred substituents or ring groups, such as aryl,heteroaryl, cycloalkyl and heterocyclyl, include halogen, alkoxy andalkyl.

A “halohydrocarbyl” is a hydrocarbyl moiety in which from one to allhydrogens have been replaced with one or more halo.

The term “halogen” or “halo” as employed herein refers to chlorine,bromine, fluorine, or iodine. As herein employed, the term “acyl” refersto an alkylcarbonyl or arylcarbonyl substituent. The term “acylamino”refers to an amide group attached at the nitrogen atom (i.e., R—CO—NH—).The term “carbamoyl” refers to an amide group attached at the carbonylcarbon atom (i.e., NH₂—CO—). The nitrogen atom of an acylamino orcarbamoyl substituent is additionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

The term “radical” as used herein means a chemical moiety comprising oneor more unpaired electrons.

A moiety that is substituted is one in which one or more hydrogens havebeen independently replaced with another chemical substituent. As anon-limiting example, substituted phenyls include 2-flurophenyl,3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 2-fluoro-3-propylphenyl.As another non-limiting example, substituted n-octyls include2,4-dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl. Included within thisdefinition are methylenes (—CH₂—) substituted with oxygen to formcarbonyl —CO—).

An “unsubstituted” moiety as defined above (e.g., unsubstitutedcycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as definedabove that does not have any of the optional substituents for which thedefinition of the moiety (above) otherwise provides. Thus, for example,while an “aryl” includes phenyl and phenyl substituted with a halo,“unsubstituted aryl” does not include phenyl substituted with a halo.

Throughout the specification, preferred embodiments of one or morechemical substituents are identified. Also preferred are combinations ofpreferred embodiments. For example, preferred embodiments of X and X¹ inthe compounds of formula (A) and preferred embodiments of R¹ in thecompounds of formula (A). Thus, also contemplated as within the scope ofthe invention are compounds of formula (A) in which X and X¹ and R¹.Furthermore, compounds excluded from any one particular genus ofcompounds (e.g., through a proviso clause) are intended to be excludedfrom the scope of the invention entirely, including from other disclosedgenera, unless expressly stated to the contrary.

Compounds

In the first aspect, the invention comprises compounds of formula (A),that are inhibitors of VEGF receptor signaling and HGF receptorsignaling:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   T is selected from the group consisting of arylalkyl, cycloalkyl,    heterocyclyl, aryl and heteroaryl, wherein each of said arylalkyl,    cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally    substituted with 1 to 3 independently selected R²⁰;-   each R²⁰ is independently selected from the group consisting of —H,    halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷, —OCF₃, —NR¹⁷R¹⁸,    —S(O)₀₋₂R¹⁷, —S(O)₂NR¹⁷R¹⁷, —C(O)OR¹⁷, —C(O)NR¹⁷R¹⁷, —N(R¹⁷)SO₂R¹⁷,    —N(R¹⁷)C(O)R¹⁷, —N(R¹⁷)C(O)OR¹⁷, —C(O)R¹⁷, —C(O)SR¹⁷, C₁-C₄ alkoxy,    C₁-C₄ alkylthio, —O(CH₂)_(n)aryl, —O(CH₂)_(n)heteroaryl,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄    alkylcarbonyl, C₁₋₄ alkoxy, an amino optionally substituted by C₁₋₄    alkyl optionally substituted by C₁₋₄ alkoxy and a saturated or    unsaturated three- to seven-membered carboxyclic or heterocyclic    group, wherein T² is selected from the group consisting of —OH,    —OMe, —OEt, —NH₂, —NHMe, —NMe₂, —NHEt and —NEt₂, and wherein the    aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are    optionally substituted;-   W is selected from the group consisting of O, S, NH and NMe;-   Z is selected from the group consisting of O, or S and NH;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano, or nitro, wherein C₁-C₆ alkyl is    optionally substituted, or-   X and X¹ taken together with the atom to which they are attached,    form a C₃-C₇ cycloalkyl;-   R¹, R², R and R⁴ independently represent hydrogen, halo,    trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷, —NR¹⁷R¹⁸, —C(O)OR¹⁷,    —C(O)R¹⁷, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₆ alkyl, C₂-C₆ alkenyl    or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆    alkynyl are optionally substituted;-   R¹⁷ is selected from the group consisting of H and R¹⁸;-   R¹⁸ is selected from the group consisting of a (C₁-C₆)alkyl, an    aryl, a aryl(C₁-C₆)alkyl, a heterocyclyl and a    heterocyclyl(C₁-C₆)alkyl, each of which is optionally substituted,    or-   R¹⁷and R¹⁸, taken together with a common nitrogen to which they are    attached, form an optionally substituted five- to seven-membered    heterocyclyl, the optionally substituted five- to seven-membered    heterocyclyl optionally containing at least one additional annular    heteroatom selected from the group consisting of N, O, S and P;-   R¹⁶ is selected from the group consisting of —H, —CN,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted    C₁₋₄alkylcarbonyl, and a saturated or unsaturated three- to    seven-membered carboxyclic or heterocyclic group, wherein T² is    selected from the group consisting of —OH, —OMe, —OEt, —NH₂, —NHMe,    —NMe₂, —NHEt and —NEt₂, and wherein the aryl, heteroaryl, C₁-C₆    alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted;-   Q is selected from the group consisting of CH₂, O, S, N(H), N(C₁-C₆    alkyl), N—Y-(aryl), —N—OMe, —NCH₂OMe and —N—Bn;-   D is selected from the group consisting of C-E and N;-   L is N, or CR, wherein R is selected from the group consisting of    —H, halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl,    wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally    substituted; and-   E is selected from the group consisting of E¹, E² and E³, wherein-   E¹ is selected from the group consisting of —H, halogen, nitro,    azido, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —C(O)NR⁴²R⁴³, —Y—NR⁴²R⁴³,    —NR⁴²C(═O)R⁴³, —SO₂R⁴², —SO₂NR⁴²R⁴³, —NR³⁷SO₂R⁴², —NR³⁷SO₂NR⁴²R⁴³,    —C(═N—OR⁴²)R⁴³, —C(═NR⁴²)R⁴³, —C(═NR⁴²)NR³⁷R⁴³,    —NR³⁷C(═NR⁴²)NR³⁷R⁴³, —C(O)R⁴², —CO₂R⁴², —C(O)(heterocyclyl),    —C(O)(C₆-C₁₀ aryl), —C(O)(heteroaryl), —Y—(C₆-C₁₀ aryl),    —Y-(heteroaryl), —Y—(5-10 membered heterocyclic), —NR^(6a)R^(6b),    —NR^(6a)SO₂R^(6b), —NR^(6a)C(O)R^(6b), —OC(O)R^(6b),    —NR^(6a)C(O)OR^(6b), —OC(O)NR^(6a)R^(6b),—OR^(6a), —SR^(6a),    —S(O)R^(6a), —SO₂R^(6a), —SO₃R^(6a), —SO₂NR^(6a)R^(6b), —SO₂NR⁴²R⁴³,    —COR^(6a), —CO₂R^(6a), —CONR^(6a)R^(6b), —(C₁-C₄)fluoroalkyl,    —(C₁-C₄)fluoroalkoxy, —(CZ³Z⁴)_(a)CN, wherein n is an integer    ranging from 0 to 6, and the aforementioned E¹ groups other than —H    and halogen are optionally substituted by 1 to 5 independently    selected R³⁸, or E¹ is selected from a moiety selected from the    group consisting of —(CZ³Z₄)_(a)-aryl, —(CZ³Z⁴)_(a)-heterocycle,    (C₂-C₆)alkynyl, —(CZ³Z⁴)_(a)—(C₃-C₆)cycloalkyl,    —(CZ³Z⁴)_(a)—(C₅-C₆)cycloalkenyl, (C₂-C₆) alkenyl and (C₁-C₆)alkyl,    which is optionally substituted with 1 to 3 independently selected    Y² groups, where a is 0, 1, 2, or 3, and wherein when a is 2 or 3,    the CZ³Z⁴ units may be the same or different; wherein-   each R³⁸ is independently selected from halo, cyano, nitro,    trifluoromethoxy, trifluoromethyl, azido, —C(O)R⁴⁰, —C(O)OR⁴⁰,    —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —NR³⁶ R³⁹, —OR³⁷,    —SO₂NR³⁶R³⁹, C₁-C₆ alkyl, —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(n)(C₆-C₁₀aryl), —(CH₂)_(n)(C₅C₁₀ heteroaryl),    —(CH₂)_(n)(5-10 membered heterocyclyl); —C(O)(CH₂)_(n)(C₆-C₁₀ aryl),    —(CH₂)_(n)O(CH₂)_(j)(C₆-C₁₀ aryl), —(CH₂)_(n)O(CH₂)_(i)(5-10    membered heterocyclyl), —C(O)(CH₂)_(n)(5-10 membered heterocyclyl),    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰,    —(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl),    —SO₂(CH₂)_(n)(5-10 membered heterocyclyl), —(CH₂)_(n)NR³⁶R³⁹,    —NR³⁷SO₂NR³⁶R³⁹, SO₂R³⁶, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl and C₁-C₆    alkylamino, wherein j is an integer ranging from 0 to 2, n is an    integer ranging from 0 to 6, i is an integer ranging from 0 to 6,    the —(CH₂)_(i)— and —(CH₂)_(n)— moieties of the foregoing R³⁸ groups    optionally include a carbon-carbon double or triple bond where n is    an integer between 2 and 6, and the alkyl, aryl, heteroaryl and    heterocyclyl moieties of the foregoing R³⁸ groups are optionally    substituted by one or more substituents independently selected from    the group consisting of halo, cyano, nitro, trifluoromethyl, azido,    —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹,    —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 membered heterocyclyl),    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and —(CH₂)_(n)OR³⁷, wherein n is an    integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;-   each R⁴² and R⁴³ is independently selected from the group consisting    of H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, —Y—(C₃-C₁₀ cycloalkyl),    —Y—(C₆-C₁₀ aryl), —Y—(C₆-C₁₀ heteroaryl), —Y—(5-10 membered    heterocyclic), —Y—O—Y¹—OR³⁷, —Y¹—CO₂—R³⁷, and —Y—OR³⁷, wherein the    alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic    moieties of the foregoing R⁴² and R⁴³ groups are optionally    substituted by 1 or more substituents independently selected from    R⁴⁴, wherein-   Y is a bond or is —(C(R³⁷)(H))_(n),-   n is an integer ranging from 1 to 6, and-   Y¹ is —(C(R³⁷)(H))_(n), or-   R⁴² and R⁴³ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted by 1 to 5 independently    selected R⁴⁴ substituents, with the proviso that R⁴² and R⁴³ are not    both bonded to the nitrogen directly through an oxygen;-   each R⁴⁴ is independently selected from the group consisting of    halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido,    —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶    R³⁹, —NR³⁶ R³⁹, —OR³⁷, —SO₂NR³⁶ R³⁹, —SO₂R³⁶, —NR³⁶SO₂R³⁹,    —NR³⁶SO₂NR³⁷R⁴¹, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀    cycloalkyl, —C₁-C₆ alkylamino, —(CH₂)_(j)O(CH₂)_(i)NR³⁶ R³⁹,    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 membered heterocyclic),    —C(O)(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)O(CH₂)j(C₆-C₁₀ aryl),    —(CH₂)_(n)O(CH₂)_(i)(5 to 10 membered heterocyclic),    —C(O)(CH₂)_(n)(5 to 10 membered heterocyclic),    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰,    —(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl), and    —SO₂(CH₂)_(n)(5 to 10 membered heterocyclic) wherein, j is an    integer from 0 to 2, n is an integer from 0 to 6 and i is an integer    ranging from 2 to 6, the —(CH₂)_(i)— and —(CH₂)_(n1)— moieties of    the foregoing R⁴⁴ groups optionally include a carbon-carbon double    or triple bond wherein n is an integer from 2 to 6, and the alkyl,    aryl and heterocyclic moieties of the foregoing R⁴⁴ groups are    optionally substituted by 1 or more substituents independently    selected from the group consisting of halo, cyano, nitro,    trifluoromethyl, azido, —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰,    —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, —SO₂R³⁶,    —SO₂NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀    aryl), —(CH₂)_(n)(5 to 10 membered heterocyclic),    —(CH₂)_(n)O(CH₂)_(i)OR³⁷ and —(CH₂)_(n)OR³⁷, wherein n is an integer    from 0 to 6 and i is an integer from 2 to 6; and-   each R⁴⁰ is independently selected from H, C₁-C₁₀ alkyl,    —(CH₂)_(n)(C₆-C₁₀ aryl), C₃-C₁₀ cycloalkyl, and —(CH₂)_(n)(5-10    membered heterocyclic), wherein n is an integer ranging from 0 to 6;-   each R³⁶ and R³⁹ is independently selected from the group consisting    of H, —OH, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl),    —(CH₂)_(n)(5-10 membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(n)CN(CH₂)_(n)OR³⁷, —(CH₂)_(n)CN(CH₂)_(n)R³⁷, and    —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i is    an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclic    moieties of the foregoing R³⁶ and R³⁹ groups are optionally    substituted by one or more substituents independently selected from    —OH, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁴⁰,    —C(O)OR⁴⁰, —CO(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁷C(O)R⁴¹, —C(O)NR³⁷R⁴¹,    —NR³⁷R⁴¹, —C₁-C₆ alkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5 to 10    membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and    —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i is    an integer ranging from 2 to 6, with the proviso that when R³⁶ and    R³⁹ are both attached to the same nitrogen, then R³⁶ and R³⁹ are not    both bonded to the nitrogen directly through an oxygen;-   each R³⁷ and R⁴¹ is independently selected from the group consisting    of H, OR³⁶, C₁-C₆ alkyl and C₃-C₁₀ cycloalkyl;-   each R^(6a) and R^(6b) is independently selected from the group    consisting of hydrogen, —(CZ⁵Z⁶)_(u)—(C₃-C₆)cycloalkyl,    —(CZ⁵Z⁶)_(u)—(C₅-C₆)cycloalkenyl, —(CZ⁵Z⁶)_(u)-aryl,    —(CZ⁵Z⁶)_(u)-heteroaryl, —(CZ⁵Z⁶)_(u)-heterocycle, (C₂-C₆)alkenyl,    and (C₁-C₆)alkyl, each of which is optionally substituted with 1 to    3 independently selected Y³ groups, where u is 0, 1, 2, or 3, and    wherein when u is 2 or 3, the CZ⁵Z⁶ units may be the same or    different, or-   R^(6a) and R^(6b) taken together with adjacent atoms can form a    heterocycle;-   each Z³, Z⁴, Z⁵ and Z⁶ is independently selected from the group    consisting of H, F and (C₁-C₆)alkyl, or-   each Z³ and Z⁴, or Z⁵ and Z⁶ are selected together to form a    carbocycle, or-   two Z³ groups on adjacent carbon atoms are selected together to    optionally form a carbocycle;-   each Y² and Y³ is independently selected from the group consisting    of halogen, cyano, nitro, tetrazolyl, guanidino, amidino,    methylguanidino, azido, —C(O)Z⁷, —OC(O)NH₂, —OC(O) NHZ⁷,    —OC(O)NZ⁷Z⁸, —NHC(O)Z⁷, —NHC(O)NH₂, —NHC(O)NHZ⁷, —NHC(O)NZ⁷Z⁸,    —C(O)OH, —C(O)OZ⁷, —C(O)NH₂, —C(O)NHZ⁷, —C(O)NZ⁷Z⁸, —P(O)₃H₂,    —P(O)₃(Z⁷)₂, —S(O)₃H, —S(O)Z⁷, —S(O)₂Z⁷, —S(O)₃Z⁷, -Z⁷, —OZ⁷, —OH,    —NH₂, —NHZ⁷, —NZ⁷Z⁸, —C(═NH)NH₂, —C(═NOH)NH₂, —N-morpholino,    (C₁-C₆)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl,    (C₂-C₆)haloalkenyl, (C₂-C₆)haloalkynyl, (C₁-C₆)haloalkoxy,    —(CZ⁹Z¹⁰)_(r)NH₂, —(CZ⁹Z¹⁰)_(r)NHZ³, —(CZ⁹Z¹⁰)_(r)NZ⁷Z⁸,    —X⁶(CZ⁹Z¹⁰)_(r)—(C₃-C₈)cycloalkyl,    —X⁶(CZ⁹Z¹⁰)_(r)—(C₁-C₈)cycloalkenyl, —X⁶(CZ⁹Z¹⁰)_(r)-aryl and    —X⁶(CZ⁹Z¹⁰)_(r)—heterocycle, wherein-   r is 1, 2, 3 or 4;-   X⁶ is selected from the group consisting of O, S, NH, —C(O)—,    —C(O)NH—, —C(O)O—, —S(O)—, —S(O)₂— and —S(O)₃—;-   Z⁷ and Z⁸ are independently selected from the group consisting of an    alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms,    an alkynyl of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon    atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14    carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7    to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or-   Z⁷ and Z⁸ together may optionally form a heterocycle;-   Z⁹ and Z¹⁰ are independently selected from the group consisting of    H, F, a (C₁-C₁₂)alkyl, a (C₆-C₁₄)aryl, a (C₅-C₁₄)heteroaryl, a    (C₇-C₁₅)aralkyl and a (C₅-C₁₄)heteroaralkyl, or-   Z⁹ and Z¹⁰ are taken together form a carbocycle, or-   two Z⁹ groups on adjacent carbon atoms are taken together to form a    carbocycle; or-   any two Y² or Y³ groups attached to adjacent carbon atoms may be    taken together to be —O[C(Z⁹)(Z¹⁰)]_(r)O or —O[C(Z⁹)(Z¹⁰)]_(r+1), or-   any two Y² or Y³ groups attached to the same or adjacent carbon    atoms may be selected together to form a carbocycle or heterocycle;    and wherein-   any of the above-mentioned substituents comprising a CH₃ (methyl),    CH₂ (methylene), or CH (methine) group which is not attached to a    halogen, SO or SO₂ group or to a N, O or S atom optionally bears on    said group a substituent selected from hydroxy, halogen,    (C₁-C₄)alkyl, (C₁-C₄)alkoxy and an —N[(C₁-C₄)alkyl][(C₁-C₄)alkyl];-   E² is —C≡CH or —C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶;-   R⁴⁵ is independently selected from the group consisting of H, a    (C₁-C₆)alkyl and a (C₃-C₈)cycloalkyl;-   R⁴⁶ is selected from the group consisting of heterocyclyl,    —N(R⁴⁷)—C(O)—N(R⁴⁷)(R⁴⁸), —N(R⁴⁷)—C(S)—N(R⁴⁷)(R⁴⁸),    —N(R⁴⁷)—C(O)—OR⁴⁸, —N(R⁴⁷)—C(O)—(CH₂)_(n)—R⁴⁸, —N(R⁴⁷)—SO₂R⁴⁷,    —(CH₂)_(n)NR⁴⁷R⁴⁸, —(CH₂)_(n)OR⁴⁸, —(CH₂)_(n)SR⁴⁹,    —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, —OC(O)R⁴⁹, —OC(O)OR⁴⁹,    —C(O)NR⁴⁷R⁴⁸, heteroaryl optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹, and aryl optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹;-   R⁴⁷ and R⁴⁸ are independently selected from the group consisting of    H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, heterocyclyl, —(CH₂)_(n)NR⁵⁰R⁵¹,    —(CH₂)_(n)OR⁵⁰, —(CH₂)_(n)C(O)R⁴⁹, —C(O)₂R⁴⁹, —(CH₂)_(n)SR⁴⁹,    —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, —(CH₂)_(n)R⁴⁹, —(CH₂)_(n)CN,    aryl optionally substituted with one or more substituents selected    from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl,    —(CH₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, and heteroaryl    optionally substituted with one or more substituents selected from    the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl,    —(CH₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, or-   R⁴⁷ and R⁴⁸, together with the atom to which they are attached, form    a 3-8 membered ring;-   R⁴⁹ is selected from the group consisting of (C₁-C₆)alkyl,    (C₃-C₈)cycloalkyl, heterocyclyl(C₁-C₆)alkylene, aryl(C₁-C₆)alkylene    wherein the aryl is optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰    R⁵¹, heteroaryl(C₁-C₆)alkylene wherein the heteroaryl is optionally    substituted with one or more substituents selected from the group    consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN,    —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, aryl optionally substituted with one    or more substituents selected from the group consisting of halo,    —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹, and heteroaryl optionally substituted with one or    more substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹;-   R⁵⁰ and R⁵¹ are independently selected from the group consisting of    H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl and —C(O)R⁴⁵, or-   R⁵⁰ and R⁵¹, together with the atom to which they are attached, form    a 3-8 membered ring; and-   E³ is the group defined by -(Z¹¹)-(Z¹²)_(m)-(Z¹³)_(m1), wherein-   Z¹¹ is heterocyclyl or heterocyclylene;-   Z¹² is selected from the group consisting of OC(O), OC(S) and C(O);-   Z¹³ is selected from the group consisting of heterocyclyl, aralkyl,    N(H)R⁵², (C₁-C₃)alkyl, —OR⁵², halo, S(O)₂R⁵⁶, (C₁-C₃)hydroxyalkyl    and (C₁-C₃)haloalkyl;-   m is 0 or 1;-   m1 is 0 or 1;-   R⁵² is selected from the group consisting of H, —(CH₂)_(q)S(O)₂R⁵⁴,    R⁵⁵NR⁵³R⁵³, (C₁-C₃)alkyl, —(CH₂)_(q)OR⁵³, —C(O)R⁵⁴ and —C(O)OR⁵³;-   q is 0, 1, 2, 3 or 4;-   R⁵³ is (C₁-C₃)alkyl;-   R⁵⁴ is (C₁-C₃)alkyl or N(H)R⁵³;-   R⁵⁵ is (C₁-C₆) alkyl; and-   R⁵⁶ is selected from the group consisting of NH₂, (C₁-C₃)alkyl and    OR⁵².

In a preferred embodiment of the compounds, T is aryl or heteroaryl,wherein each of said aryl and heteroaryl is optionally substituted with1 to 3 independently selected R²⁰.

In a preferred embodiment of the compounds, T is selected from the groupconsisting of arylalkyl, cycloalkyl and heterocyclyl, wherein each ofsaid arylalkyl, cycloalkyl and heterocyclyl is optionally substitutedwith 1 to 3 independently selected R²⁰.

In a preferred embodiment of the compounds, R²⁰ is selected from thegroup consisting of H, halogen, —OR¹⁷ and —C(O)OR¹⁷.

In a preferred embodiment of the compounds, R²⁰ is fluorine or chloride.

In a preferred embodiment of the compounds, W is O.

In a preferred embodiment of the compounds, Z is S or O.

In a preferred embodiment of the compounds, Z is S.

In a preferred embodiment of the compounds, X and X¹ are independentlyselected from the group consisting of H and C₁-C₆alkyl, wherein theC₁-C₆alkyl is optionally substituted.

In a preferred embodiment of the compounds, X and X¹ are both H.

In a preferred embodiment of the compounds, X and X¹ taken together withthe atom to which they are attached, form a C₃-C₇cycloalkyl.

In a preferred embodiment of the compounds, R¹, R², R³ and R⁴ areindependently selected from the group consisting of H, halogen,trihalomethyl, OR¹⁷, —NR¹⁷R¹⁸ and C₁-C₆alkyl.

In a preferred embodiment of the compounds, R¹, R² and R⁴ areindependently selected from the group consisting of H, halo and —OR¹⁷.

In a preferred embodiment of the compounds, R¹ is H or halogen.

In a preferred embodiment of the compounds, R¹ is halogen.

In a preferred embodiment of the compounds, R², R³ and R⁴ are each H.

In a preferred embodiment of the compounds, R¹⁷ is a C₁-C₆alkyl.

In a preferred embodiment of the compounds, R¹⁶ is H or C₁-C₆alkyl.

In a preferred embodiment of the compounds, Q is selected from the groupconsisting of CH₂, S, —N—(C₁-C₆alkyl), N—Y-(aryl) and —N—OMe.

In a preferred embodiment of the compounds, Q is S.

In a preferred embodiment of the compounds, Q is CH₂.

In a preferred embodiment of the compounds, Q is —N—(C₁-C₆alkyl).

In a preferred embodiment of the compounds, Q is —N—Y-(aryl).

In a preferred embodiment of the compounds, Q is —N—OMe.

In a preferred embodiment of the compounds, D is C-E.

In a preferred embodiment of the compounds, D is CH.

In a preferred embodiment of the compounds, L is C—R.

In a preferred embodiment of the compounds, R is H or halogen.

In a preferred embodiment of the compounds, L is N.

In a preferred embodiment of the compounds, E is selected from the groupconsisting of E¹ and E².

In a preferred embodiment of the compounds, E is E¹.

In a preferred embodiment of the compounds, E is E¹, wherein E¹ isselected from the group consisting of H, halogen, —C(O)NR⁴²R⁴³,—SO₂NR⁴²R⁴³, C(═NR⁴²)NR³⁷R⁴³, —CO₂R⁴², —C(O)(heterocyclyl),—C(O)(heteroaryl), —Y—(C₆-C₁₀ aryl), —Y-(heteroaryl), —Y-(5 to 10membered heterocyclic), —SR^(6a), —S(O)R^(6a), —SO₂R^(6a), wherein eachof said E¹ other than H and halogen are optionally substituted with 1 to5 independently selected R³⁸, or E1 is (C1-C6)alkyl, which is optionallysubstituted with 1 to 3 independently selected Y2 groups.

In a preferred embodiment of the compounds, R³⁸ is selected from thegroup consisting of halogen, —C(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶ R³⁹,—NR³⁶R³⁹, —OR³⁷, C₁-C₆alkyl, —C(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,—(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆alkyl), —(CH₂)_(n)-(5 to 10 memberedheterocyclic), —(CH₂)O(CH₂)_(i)(5 to 10 membered heterocyclic),—(CH₂)_(n)(5 to 10 membered heteroaryl), —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹,—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —(CH₂)_(n)NR³⁶R³⁹, wherein j is an integerranging from 0 to 2, n is an integer ranging from 0 to 6, i is aninteger ranging from 1 to 6, the —(CH₂)_(i)— and —(CH₂)_(n)— moieties ofthe foregoing R³⁸ groups optionally include a carbon-carbon double ortriple bond where n is an integer between 2 and 6, and the alkyl, aryl,heteroaryl, and heterocyclic moieties of the foregoing R³⁸ groups areoptionally substituted by one or more substituents independentlyselected from the group consisting of halo, cyano, nitro,trifluoromethyl, azido, —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰,—NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 memberedheterocyclyl), —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and —(CH₂)_(n)OR³⁷, wherein nis an integer ranging from 0 to 6 and i is an integer ranging from 2 to6.

In a preferred embodiment of the compounds, the alkyl, aryl, heteroaryl,and heterocyclic moieties of the foregoing R³⁸ groups are optionallysubstituted by one or more substituents independently selected from thegroup consisting of —OH and —C(O)OR⁴⁰.

In a preferred embodiment of the compounds, each R⁴² and R⁴³ isindependently selected from the group consisting of H, —Y—(C₃-C₁₀cycloalkyl), —Y—(C₆-C₁₀ aryl), —Y—(C₆-C₁₀ heteroaryl) and —Y-(5 to 10membered heterocyclic), wherein the cycloalkyl, aryl, heteroaryl andheterocyclic moieties of the foregoing R⁴² and R⁴³ groups are optionallysubstituted by 1 or more substituents independently selected from R⁴⁴.

In a preferred embodiment of the compounds, each R⁴² and R⁴³ isindependently selected from the group consisting of H, C₁-C₆ alkyl,C₁-C₆ heteroalkyl, —Y¹—CO₂—R³⁷ and —Y—OR³⁷.

In a preferred embodiment of the compounds, one of R⁴² and R⁴³ is H.

In a preferred embodiment of the compounds, one of R⁴² and R⁴³ is—(C₆-C₁₀ heteroaryl) or —Y-(5 to 10 membered heterocyclic).

In a preferred embodiment of the compounds, Y is a bond.

In a preferred embodiment of the compounds Y is —(C(R³⁷)(H))_(n).

In a preferred embodiment of the compounds, R⁴² and R⁴³ taken togetherwith the nitrogen to which they are attached form a C₅-C₉ heterocyclylring or a heteroaryl ring, wherein said ring is optionally substitutedby 1 to 5 independently selected R⁴⁴ substituents, with the proviso thatR⁴² and R⁴³ are not both bonded to the nitrogen directly through anoxygen.

In a preferred embodiment of the compounds, R⁴⁴ is independentlyselected from the group consisting of —C(O)NR³⁶R³⁹, —OR³⁷ andC₁-C₆alkyl.

In a preferred embodiment of the compounds, each R⁴⁰ is independentlyselected from the group consisting of H and C₁-C₁₀ alkyl.

In a preferred embodiment of the compounds, each R³⁶ and R³⁹ isindependently selected from the group consisting of H, C₁-C₆alkyl,—(CH₂)_(n)(5 to 10 membered heterocyclic), —(CH₂)_(n)OR³⁷ and —C(O)OR⁴⁰,wherein n is an integer ranging from 0 to 6 and i is an integer rangingfrom 2 to 6, with the proviso that when R³⁶ and R³⁹ are both attached tothe same nitrogen, then R³⁶ and R³⁹ are not both bonded to the nitrogendirectly through an oxygen.

In a preferred embodiment of the compounds, each R³⁷ and R⁴¹ isindependently selected from the group consisting of H and C₁-C₆alkyl.

In a preferred embodiment of the compounds, R^(6a) is selected from thegroup consisting of —(CZ⁵Z⁶)_(u)-aryl, —(CZ⁵Z⁶)_(u)-heteroaryl andC₁-C₆alkyl, each of which is optionally substituted with 1 to 3independently selected Y³ groups, wherein u is 0, 1, 2 or 3, and whereinwhen u is 2 or 3, the CZ⁵Z⁶ units may be the same or different.

In a preferred embodiment of the compounds, R^(6a) is selected from thegroup consisting of —(CZ⁵Z⁶)_(u)-aryl and —(CZ⁵Z⁶)_(u)-heteroaryl, eachof which is optionally substituted with 1 to 3 independently selected Y³groups, wherein u is 0.

In a preferred embodiment of the compounds, Y² is —OH.

In a preferred embodiment of the compounds, Y³ is —OH.

In a preferred embodiment of the compounds, E² is—C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶, wherein n is an integer ranging from 1 to 6.

In a preferred embodiment of the compounds, R⁴⁵ is H.

In a preferred embodiment of the compounds, R⁴⁶ is a heterocyclyl.

In a preferred embodiment of the compounds, the compounds arerepresented by the formula A-0:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   Z is O or S;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano and nitro, wherein C₁-C₆ alkyl is    optionally substituted;-   R¹, R², R³ and R⁴ are independently selected from the group    consisting of hydrogen, halo, trihalomethyl, —OR¹⁷, C₁-C₆ alkyl,    C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl    and C₂-C₆ alkynyl are optionally substituted;-   Q is O, S, NH, N(C₁-C₆ alkyl), or N—Y-(aryl);-   D is CR¹¹, or N;-   L is N, or CR, wherein R is H, halo, —CN, C₁-C₆ alkyl, C₂-C₆    alkenyl, or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and    C₂-C₆ alkynyl are optionally substituted; and-   R⁷ is H, halogen, C₁-C₆ alkyl, —C(═O)NR⁹R¹⁰, —C(═O)(aryl),    —C(═O)(heterocyclyl), —C(═O)(heteroaryl), —Y-(aryl),    —Y-(heterocyclyl), —Y-(heteroaryl), —S-aryl, —S—C₁-C₆ alkyl,    —SO—C₁-C₆ alkyl, —SO₂—C₁-C₆ alkyl, —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰ or CO₂R⁹,    wherein C₁-C₆ alkyl, aryl, heterocycle and heteroaryl are each    independently optionally substituted;-   R⁹ and R¹⁰ are independently selected from H, C₁-C₆ alkyl,    —Y-(cycloalkyl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —Y—o—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹, and —Y—O—R¹¹, wherein C₁-C₆ alkyl,    cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally    substituted, or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y¹ is —(C(R¹¹)(H))_(t)—,-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted,-   each R²⁰ is independently selected from the group consisting of    hydrogen, halo, trihalomethyl, OR¹⁷, C₁-C₆ alkyl, C₂-C₆ alkenyl or    C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl    are optionally substituted, and-   each R¹⁷ is an independently selected C₁-C₆alkyl, wherein said    C₁-C₆alkyl is optionally substituted.

In a preferred embodiment of the compounds, X and X¹ are both hydrogen.

In a preferred embodiment of the compounds, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds, R¹ is fluorine.

In a preferred embodiment of the compounds, R⁴ is hydrogen or halogen.

In a preferred embodiment of the compounds, R⁴ is fluorine.

In a preferred embodiment of the compounds, R² is selected from thegroup consisting of H, halogen, trihalomethyl and —OR¹⁷.

In a preferred embodiment of the compounds, R³, and R²⁰ are eachhydrogen.

In a preferred embodiment of the compounds, R²⁰ is —OR¹⁷.

In a preferred embodiment of the compounds, Q is S, N(C₁-C₆ alkyl), orN—Y-(aryl).

In a preferred embodiment of the compounds, Q is NH.

In a preferred embodiment of the compounds, D is CR¹¹.

In a preferred embodiment of the compounds, L is CH or N.

In a preferred embodiment of the compounds, R⁷ is H, halogen, C₁-C₆alkyl, —CONR⁹R¹⁰, —SO₂NH₂, —SO₂NR⁹R¹⁰, −Y-heterocyclyl, —Y-heteroaryl,—S-aryl, —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, or —SO₂—C₁-C₆ alkyl, whereinC₁-C₆ alkyl, is unsubstituted or is substituted with one or two ofhydroxy or halogen, and heterocyclyl, and heteroaryl are unsubstitutedor substituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, R⁷ is —CONR⁹R¹⁰.

In a preferred embodiment of the compound, R⁷ is Y-heteroaryl.

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are independentlyH, C₁-C₆ alkyl, —Y—O—R¹¹, —Y-(heterocycle), —Y¹—CO₂—R¹¹, or —Y-(aryl),wherein C₁-C₆ alkyl is unsubstituted or is substituted with one or twoof hydroxy or halogen, and heterocyclyl, and aryl are unsubstituted orare substituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are takentogether with the nitrogen to which they are attached to form apyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinylring, wherein said ring is unsubstituted or is substituted with one ortwo of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, R⁷ is H, halogen, C₁-C₆alkyl, —SO₂NR⁹R¹⁰, —C(═O)(heterocyclyl),13 Y-(heterocyclyl), or—Y-(heteroaryl), wherein C₁-C₆ alkyl is unsubstituted or is substitutedwith one or two of hydroxy or halogen, and heterocyclyl, and heteroarylare unsubstituted or are substituted with one or two of alkoxy, alkyl,or haloalkyl.

In a preferred embodiment of the compounds, Z is sulfur.

In a preferred embodiment of the compounds, the compounds arerepresented by the formula A-1:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   X and X¹ are independently selected from the group consisting of H    and C₁-C₆ alkyl, wherein C₁-C₆ alkyl is optionally substituted, or-   X and X¹ taken together with the atom to which they are attached,    form a C₃-C₇ cycloalkyl;-   R⁷ is H, halogen, C₁-C₆ alkyl, —C(═O)NR⁹R¹⁰, —C(═O)(aryl),    —C(═O)(heterocyclyl), —C(═O)(heteroaryl), —Y-(aryl),    —Y-(heterocyclyl), —Y-(heteroaryl), —SR^(6a), —S-aryl,    —S-(heteroaryl), —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, —SO₂—C₁-C₆ alkyl,    −Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰, CO₂R⁹, —C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶ and    —C(═NR⁴²)NR³⁷R⁴³, wherein n is an integer ranging from 0 to 6 and    wherein C₁-C₆ alkyl, aryl, heterocycle and heteroaryl are each    independently optionally substituted with 1 to 5 independently    selected R³⁸;-   R⁹ and R¹⁰ are independently selected from H, C₁-C₆ alkyl,    —Y-(cycloalkyl), —Y—(C₁-C₆ heteroalkyl), —Y-(aryl),    —Y-(heterocyclyl), —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R ¹¹,    Y—C(O)OR³⁷ and —Y—O—R¹¹, wherein said C₁-C₆ alkyl,heteroalkyl,    cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally    substituted with one or more independently selected R⁴⁴, or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted with 1 to 5    independently selected R⁴⁴;-   each R²⁰ is independently selected from the group consisting of H,    halo, —OR¹⁷ and —C(O)OR¹⁷;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y¹ is —(C(R¹¹)(H))_(t)—, and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds, R¹ is fluorine.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, —C(═O)NR⁹R¹⁰, —Y-(aryl), —Y-(heteroaryl) and—S—C₁-C₆ alkyl, wherein said —Y-(aryl), —Y-(heteroaryl) and —S—C₁-C₆alkyl are optionally substituted with 1 to 5 independently selected R³⁸.

In a preferred embodiment of the compounds, R⁷ is —C(═O)NR⁹R¹⁰,optionally substituted with one or more independently selected R⁴⁴.

In a preferred embodiment of the compounds, R⁷ is —Y-(aryl), optionallysubstituted with 1 to 5 independently selected R³⁸.

In a preferred embodiment of the compounds, R⁷ is —Y-(heteroaryl),optionally substituted with 1 to 5 independently selected R³⁸.

In a preferred embodiment of the compounds, R³⁸ is selected from thegroup consisting of halogen, —OR³⁷, C₁-C₆alkyl, —(CH₂)_(n)-(5 to 10membered heterocyclyl), —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,—(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(n)— heteroaryl, —C(O)NR³⁶R³⁹,—(CH₂)_(n)O(CH₂)_(i)(5to 10 membered heterocyclyl) and—(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹, wherein n is an integer ranging from 0 to6, j is an integer ranging from 0 to 2 , j is an integer ranging from 1to 6 and wherein the alkyl, heteroaryl and heterocyclyl moieties of theforegoing R³⁸ groups are optionally substituted by one or moresubstituents independently selected from the group consisting of halo,cyano, nitro, trifluoromethyl, azido, —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰,—OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10membered heterocyclyl), —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and —(CH₂)_(n)OR³⁷,wherein n is an integer ranging from 0 to 6 and i is an integer rangingfrom 2 to 6.

In a preferred embodiment of the compounds, R³⁸ is selected from thegroup consisting of —OR³⁷, C₁-C₆alkyl, —(CH₂)_(n)(5 to 10 memberedheterocyclyl) and —(CH₂)_(n)O(CH₂)_(i)(5 to 10 membered heterocyclyl).

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, —C₁-C₆heteroalkyl, —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl), —Y—O—R¹¹ andY—C(O)OR³⁷, wherein a C₁-C₆ alkyl, C₁-C₆ heteroalkyl, aryl,heterocyclcyl and heteroaryl are each optionally substituted with 1 ormore independently selected R⁴⁴.

In a preferred embodiment of the compounds, R⁴⁴ is selected from thegroup consisting of C₁-C₆ alkyl, —OR³⁷, —C(O)NR³⁶R³⁹ and —C(O)OR⁴⁶.

In a preferred embodiment of the compounds, R³⁶ is selected from thegroup consisting of H, C₁-C₆ alkyl, —(CH₂)_(n)OR³⁷ and—(CH₂)_(n)(heterocyclyl).

In a preferred embodiment of the compounds, R³⁹ is H or C₁-C₆ alkyl.

In a preferred embodiment of the compounds, R³⁷ is H or C₁-C₆ alkyl.

In a preferred embodiment of the compounds, R²⁰ is selected from thegroup consisting of H, halogen, —OR¹⁷ and —C(O)OR¹⁷.

In a preferred embodiment of the compounds, R¹⁷ is H or C₁-C₆ alkyl.

In a preferred embodiment of the compounds, R²⁰ is halogen.

In a preferred embodiment of the compounds, R²⁰ is Cl or F.

In a preferred embodiment of the compounds, R^(6a) is —(CZ⁵Z⁶)_(u)-aryl.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, halogen, C₁-C₆ alkyl, —CONR⁹R¹⁰, —SO₂NH₂,—SO₂NR⁹R¹⁰, —Y-heterocyclyl, —Y-heteroaryl, —S-aryl, —S—C₁-C₆ alkyl,—SO—C₁-C₆ alkyl, or —SO₂—C₁-C₆ alkyl, wherein C₁-C₆ alkyl isunsubstituted or is substituted with one or two of hydroxy or halogen,and the heterocyclyl, and heteroaryl are unsubstituted or aresubstituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, halogen, C₁-C₆ alkyl, —SO₂NR⁹R¹⁰,—C(═O)(heterocyclyl), —Y-(heterocyclyl), —Y-(heteroaryl), —S-aryl,—S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, or —SO₂—C₁-C₆ alkyl, wherein C₁-C₆alkyl is unsubstituted or is substituted with one or two of hydroxy orhalogen, and the heterocyclyl, and heteroaryl are unsubstituted or aresubstituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl,—Y—O—R¹¹, —Y-(heterocycle), —Y—CO₂—R¹¹, —Y-(aryl) and —Y-(heteroaryl),wherein C₁-C₆ alkyl is unsubstituted or is substituted with one or twoof hydroxy or halogen, and the heterocyclyl, aryl and heteroaryl areunsubstituted or are substituted with one or two of alkoxy, alkyl, orhaloalkyl.

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are takentogether with the nitrogen to which they are attached to form apyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinylring, wherein said ring is unsubstituted or is substituted with one ortwo of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, NR⁹R¹⁰ is selected from:

In a preferred embodiment of the compounds R⁷ is unsubstitutedheteroaryl.

In a preferred embodiment of the compounds, R⁷ is thiazolyl, pyridinyl,pyrimidinyl, and imidazolyl, each of which is preferably unsubstitutedor is substituted with one or two of alkoxy, or alkyl.

In a preferred embodiment of the compounds, R⁷ is C₁-C₆ alkyl,unsubstituted or substituted with hydroxy.

In a preferred embodiment of the compounds, X and X¹ are both H.

In a preferred embodiment of the compounds, R¹⁷ is selected from thegroup consisting of H and C₁-C₆ alkyl.

In a preferred embodiment of the compounds, R³⁸ is selected from thegroup consisting of —OR³⁷, C₁-C₆ alkyl and —(CH₂)_(n)(5 to 10 memberedheterocylic), wherein n is an integer ranging from 0 to 6.

In a preferred embodiment of the compounds, R³⁷ is selected from thegroup consisting of H and C₁-C₆ alkyl.

In a preferred embodiment of the compounds, the compounds arerepresented by the formula A-2:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R⁷ is selected from the group consisting of H, halogen, C₁-C₆ alkyl,    —C(═O)NR⁹R¹⁰, —C(═O)(aryl), —C(═O)(heterocyclyl),    —C(═O)(heteroaryl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —S-aryl, —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, —SO₂—C₁-C₆ alkyl,    —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰ and CO₂R⁹, wherein C₁-C₆ alkyl, aryl,    heterocycle and heteroaryl are each independently optionally    substituted with 1 to 5 independently selected R³⁸;-   R⁹ and R¹⁰ are independently selected from the group consisting of    H, C₁-C₆ alkyl, —Y-(cycloalkyl), —Y-(aryl), —Y-(heterocyclyl),    —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹ and —Y—O—R¹¹, wherein    C₁-C₆ alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each    optionally substituted with one or more independently selected R⁴⁴,    or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y₁ is —(C(R¹¹)(H))_(t)—, and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds, R¹ R1 is fluorine.

In a preferred embodiment of the compounds, R⁴ is selected from thegroup consisting of H and halogen.

In a preferred embodiment of the compounds, R⁴ is fluorine.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, halogen, C₁-C₆ alkyl, —C(═O)NR⁹R¹⁰, —SO₂NH₂,—SO₂NR⁹R¹⁰, —Y-heterocyclyl —Y-heteroaryl, —S-aryl, —S—C₁-C₆ alkyl,—SO—C₁-C₆ alkyl and —SO₂—C₁-C₆ alkyl, wherein C₁-C₆ alkyl, heterocyclyl,heteroaryl and aryl are each optionally substituted with 1 to 5independently selected R³⁸.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, halogen, C₁-C₆ alkyl, —C(═O)NR⁹R¹⁰, —SO₂NH₂,—SO₂NR⁹R¹⁰, —Y-heterocyclyl —Y-heteroaryl, —S-aryl, —S—C₁-C₆ alkyl,—SO—C₁-C₆ alkyl and —SO₂—C₁-C₆ alkyl, wherein C₁-C₆ alkyl isunsubstituted or is substituted with one or two of hydroxy or halogen,and the heterocyclyl, and heteroaryl are unsubstituted or aresubstituted with one or two of alkoxy, alkyl, haloalkyl or(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, halogen, C¹-C⁶ alkyl, —SO₂NR⁹R¹⁰,—C(═O)(heterocyclyl), —Y-(heterocyclyl), —Y-(heteroaryl), —S-aryl,—S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, or —SO₂—C₁-C₆ alkyl, wherein C₁-C₆alkyl is unsubstituted or is substituted with one or two of hydroxy orhalogen, and the heterocyclyl, and heteroaryl are unsubstituted or aresubstituted with one or two of alkoxy, alkyl, haloalkyl or(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of C₁-C₆ alkyl, —C(═O)NR⁹R¹⁰, —Y-(heterocyclyl,—Y-(heteroaryl), —S—C₁-C₆ alkyl and —SO—C₁-C₆ alkyl, wherein C₁-C₆ alkylis unsubstituted or is substituted with one or two of hydroxy orhalogen, and the heterocyclyl, and heteroaryl are unsubstituted or aresubstituted with one or two of alkoxy, alkyl, haloalkyl or(CH₂)_(j)NR₃₉(CH₂)_(n)O(CH₂)_(i)OR³⁷.

In a preferred embodiment of the compounds, R₇ is CONR⁹R¹⁰.

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, —Y—O—R₁₁,—Y-(heterocycle), —Y¹—CO₂—R¹¹ and —Y-(aryl), wherein the alkyl,heterocyclyl and aryl moieties of the foregoing R₉ and R₁₀ groups areoptionally substituted with 1 or more substituents independentlyselected from R^(44.)

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, —Y—O—R¹¹,—Y-(heterocycle), —Y¹—CO₂—R¹¹ and —Y-(aryl), wherein C¹-C⁶ alkyl, isunsubstitued or is substituted with one or two of hydroxy or halogen,and the heterocyclyl, and aryl are unsubstitued or are substituted withone or two of alkoxy, alkyl, haloalkyl or(CH₂)_(j)NR₃₉(CH₂)_(n)O(CH₂)_(i)OR³⁷.

In a preferred embodiment of the compounds, R⁹ and R¹⁰ taken togetherwith the nitrogen to which they are attached form a C₅-C₉ heterocyclylring or a heteroaryl ring, wherein said ring is optionally substituted.

In a preferred embodiment of the compounds, R₉ R₁₀ are taken togetherwith the nitrogen to which they are attached to form a pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring, whereinsaid ring is unsubstituted or is substituted with one or two of alkoxy,alkyl, or haloalkyl.

In a preferred embodiment of the compounds, NR⁹R¹⁰ is selected from thegroup consisting of:

In a preferred embodiment of the compounds, the compounds arerepresented by the formula A-3:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   R⁷ is selected from the group consisting of H, —Y-(aryl) and    —Y-(heteroaryl), wherein —Y-(aryl) and —Y-(heteroaryl) are    optionally substituted with 1 to 5 independently selected R³⁸;-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R¹² is selected from the group consisting of H, C₁-C₆ alkyl,    —O(C₁-C₆ alkyl) and —Y-(aryl), wherein C₁-C₆ alkyl and aryl are    optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   R¹¹ is H or C₁-C₆ alkyl, wherein C₁-C₆ alkyl is optionally    substituted; and each R₂₀ is independently selected from the group    consisting of H and halogen.

In a preferred embodiment of the compounds, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds, R¹ is fluorine.

In a preferred embodiment of the compounds, R¹² is unsubstituted C₁-C₃alkyl or unsubstituted —Y-phenyl.

In a preferred embodiment of the compounds, R²⁰ is Cl.

In a preferred embodiment of the compounds, the compounds arerepresented by the formula A-4:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   Z is O or S;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano and nitro, wherein C₁-C₆ alkyl is    optionally substituted;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently selected from the group    consisting of hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆    alkynyl and NR¹⁷R¹⁸, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆    alkynyl are optionally substituted;-   R¹⁷ and R¹⁸ are independently C₁-C₆alkyl;-   Q is O, S, NH, N(C₁-C₆ alkyl), or N—Y-(aryl);-   D is CR¹¹, or N;-   L is N, or CR, wherein R is selected from the group consisting of H,    halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl, wherein    C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally    substituted; and-   R¹³ is heterocyclyl or heteroaryl, wherein heterocyclyl and    heteroaryl are optionally substituted with 1 to 5 independently    selected R³⁸;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6; and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds, X and X¹ are both hydrogen.

In a preferred embodiment of the compounds, R¹, R², R³ and R⁴ areindependently H or halogen.

In a preferred embodiment of the compounds, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds, R¹ is fluorine or chlorine.

In a preferred embodiment of the compounds, R⁴ is hydrogen or halogen.

In a preferred embodiment of the compounds, R⁴ is fluorine or chlorine.

In a preferred embodiment of the compounds, R², R³, R⁵, and R⁶ are eachhydrogen.

In a preferred embodiment of the compounds, Q is selected from the groupconsisting of S, N(C₁-C₆ alkyl) and N—Y-(aryl).

In a preferred embodiment of the compounds, Q is S.

In a preferred embodiment of the compounds, D is CR¹¹.

In a preferred embodiment of the compounds, R¹¹ is H.

In a preferred embodiment of the compounds, L is CH or N.

In a preferred embodiment of the compounds, L is CH.

In a preferred embodiment of the compounds, Z is sulfur.

In a preferred embodiment of the compounds, R³⁸ is selected fromC(O)OR⁴⁰ and NR³⁶R³⁹.

In a preferred embodiment of the compounds, R⁴⁰ is H or C₁-C₁₀ alkyl.

In a preferred embodiment of the compounds, R³⁶ and R³⁹ areindependently C₁-C₆ alkyl.

In a preferred embodiment of the compounds, the compounds arerepresented by the formula A-5:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   R⁷ is selected from the group consisting of H, —C(O)NR⁴²R⁴³,    —Y-(aryl), —Y-(heteroaryl), —C(O)—(C₃-C₁₀ cycloalkyl),    —C(O)-(heterocyclyl), —C(O)—(C₆-C₁₀ aryl) and —C(O)-(heteroaryl),    wherein the aforementioned R⁷ groups other than H are optionally    substituted with 1 to 5 independently selected R³⁸;-   R⁴ is selected from the group consisting of H and halogen; and-   T is selected from the group consisting of cycloalkyl, heterocyclyl,    aryl, heteroaryl and arylalkyl, each of which is optionally    substituted with 1 to 3 independently selected R²⁰;

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, C(O)NR⁴²R⁴³ and —Y-(heteroaryl), wherein—Y-(heteroaryl) is optionally substituted with 1 to 5 independentlyselected R³⁸;

In a preferred embodiment of the compounds, R⁷ is C(O)NR⁴²R⁴³;

In a preferred embodiment of the compounds, R⁴² and R⁴³ taken togetherwith the nitrogen to which they are attached form a C₅-C₉ heterocyclylring, wherein said ring is optionally substituted with 1 to 5independently selected R⁴⁴ substituents, with the proviso that R⁴² andR⁴³ are not both bonded to the nitrogen directly through and oxygen.

In a preferred embodiment of the compounds, R⁴ is halogen.

In a preferred embodiment of the compounds, R⁴ is fluorine.

In a preferred embodiment of the compounds, the compounds arerepresented by the formula A-6:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R⁷ is selected from the group consisting of H, halogen, C₁-C₆ alkyl,    —C(═O)NR⁹R¹⁰, —C(═O)(aryl), —C(═O)(heterocyclyl),    —C(═O)(heteroaryl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —SR^(6a), —S-aryl, —S-(heteroaryl), —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl,    —SO₂—C₁-C₆ alkyl, —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰, CO₂R⁹,    —C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶ and —C(═NR⁴²)NR³⁷R⁴³, wherein n is an integer    ranging from 0 to 6 and wherein C₁-C₆ alkyl, aryl, heterocycle and    heteroaryl are each independently optionally substituted with 1 to 5    independently selected R³⁸;-   R⁹ and R¹⁰ are independently selected from the group consisting of    H, C₁-C₆ alkyl, —Y-(cycloalkyl), —Y—(C₁-C₆ heteroalkyl), —Y-(aryl),    —Y-(heterocyclyl), —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹,    Y—C(O)OR³⁷ and —Y—O—R¹¹, wherein said C₁-C₆ alkyl, heteroalkyl,    cycloalkyl, aryl, heterocycle, and heteroaryl are each optionally    substituted with one or more independently selected R⁴⁴, or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted with 1 to 5    independently selected R⁴⁴;-   each R²⁰ is independently selected from the group consisting of H,    halo, —OR¹⁷ and —C(O)OR¹⁷;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y¹ is —(C(R¹¹)(H))_(t)—; and-   R¹¹ at each occurrence is independently H or C₁- C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, C(O)NR⁹R¹⁰ and —Y-(heteroaryl), wherein—Y-(heteroaryl) is optionally substituted with 1 to 5 independentlyselected R³⁸;

In a preferred embodiment of the compounds, R⁷ is C(O)NR⁹R¹⁰;

In a preferred embodiment of the compounds, R⁹ and R¹⁰ taken togetherwith the nitrogen to which they are attached form a C₅-C₉ heterocyclylring, wherein said ring is optionally substituted with 1 to 5independently selected R⁴⁴ substituents.

In a preferred embodiment of the compounds, R⁷ is —Y-(heteroaryl),wherein said —Y-(heteroaryl) is optionally substituted with 1 to 5independently selected R³⁸.

In a preferred embodiment of the compounds, R⁷ is —Y-(heteroaryl),wherein said —Y-(heteroaryl) is optionally substituted with one C₁-C₆alkyl.

In a preferred embodiment of the compounds, R¹ is halogen.

In a preferred embodiment of the compounds, R¹ is fluorine.

In a preferred embodiment of the compounds, R¹⁷ is selected from thegroup consisting of H and C₁-C₆ alkyl.

In a preferred embodiment of the compounds, R³⁸ is selected from thegroup consisting of —OR³⁷, C₁-C₆ alkyl and —(CH₂)_(n)(5 to 10 memberedheterocylic), wherein n is an integer ranging from 0 to 6.

In a preferred embodiment of the compounds, R³⁷ is selected from thegroup consisting of H and C₁-C₆ alkyl.

In a preferred embodiment of the compounds, each R²⁰ is independentlyselected from the group consisting of H, halogen and —O—(C₁-C₆)alkyl.

In a preferred embodiment of the compounds, two R²⁰ are H and the thirdR²⁰ is selected from the group consisting of H, halogen and —O—(C₁-C₆alkyl).

In a second aspect, the invention comprises compounds of formula (B),which are inhibitors of VEGF receptor signaling and HGF receptorsignaling:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   T is selected from the group consisting of cycloalkyl, heterocyclyl,    aryl and heteroaryl, wherein each of said cycloalkyl, heterocyclyl,    aryl and heteroaryl is optionally substituted with 1 to 3 R²⁰;-   each R²⁰ is independently selected from the group consisting of —H,    halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷, —OCF₃, —NR¹⁷R¹⁸,    —S(O)₀₋₂R¹⁷, —S(O)₂NR¹⁷R¹⁷, —C(O)OR¹⁷, —C(O)NR¹⁷R¹⁷, —N(R¹⁷)SO₂R¹⁷,    —N(R¹⁷)C(O)R¹⁷, —N(R¹⁷)C(O)OR¹⁷, —C(O)R¹⁷, —C(O)SR¹⁷, C₁-C₄ alkoxy,    C₁-C₄ alkylthio, —O(CH₂)_(n)aryl, —O(CH₂)_(n)heteroaryl,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄    alkylcarbonyl, C₁₋₄ alkoxy, an amino optionally substituted by C₁₋₄    alkyl optionally substituted by C₁₋₄ alkoxy and a saturated or    unsaturated three- to seven-membered carboxyclic or heterocyclic    group, wherein T² is selected from the group consisting of —OH,    —OMe, —OEt, —NH₂, —NHMe, —NMe₂, —NHEt and —NEt₂, and wherein the    aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are    optionally substituted;-   W is selected from the group consisting of O, S and NH;-   Z is selected from the group consisting of O, or S and NH;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano, or nitro, wherein C₁-C₆ alkyl is    optionally substituted, or-   X and X¹ taken together with the atom to which they are attached,    form a C₃-C₇ cycloalkyl;-   R¹, R², R³ and R⁴ are independently selected from the group    consisting of hydrogen, halo, trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷,    —NR¹⁷R¹⁸, —C(O)OR¹⁷, —C(O)R¹⁷, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₆    alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R¹⁷ is selected from the group consisting of H and R¹⁸;-   R¹⁸ is selected from the group consisting of a C₁-C₆ alkyl, an aryl,    an aryl(C₁-C₆ alkyl), a heterocyclyl and a heterocyclyl(C₁-C₆    alkyl), each of which is optionally substituted, or-   R¹⁷ and R¹⁸, taken together with a common nitrogen to which they are    attached, form an optionally substituted five- to seven-membered    heterocyclyl, the optionally substituted five- to seven-membered    heterocyclyl optionally containing at least one additional annular    heteroatom selected from the group consisting of N, O, S and P;-   R¹⁶ is selected from the group consisting of —H, —CN,    —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,    C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄    alkylcarbonyl, and a saturated or unsaturated three- to    seven-membered carboxyclic or heterocyclic group, wherein T² is    selected from the group consisting of —OH, —OMe, —OEt, —NH₂, —NHMe,    —NMe₂, —NHEt and —NEt₂, and wherein the aryl, heteroaryl, C₁-C₆    alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally substituted;-   Q is selected from the group consisting of CH₂, O, S, NH, N—(C₁-C₆    alkyl), or N—Y-(aryl), —N—OMe, —NCH₂OMe and —N—Bn;-   D is selected from the group consisting of C-E and N;-   L is N, or CR, wherein R is selected from the group consisting of    —H, halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl,    wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionally    substituted; and-   E is selected from the group consisting of E¹, E² and E³, wherein-   E¹ is selected from the group consisting of —H, halogen, nitro,    azido, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —C(O)NR⁴²R⁴³, —Y—NR⁴²R⁴³,    —NR⁴²C(═O)R⁴³, —SO₂R⁴², —SO₂NR⁴²R⁴³, —NR ³⁷SO₂R⁴², —NR³⁷SO₂NR⁴²R⁴³,    —C(═N—OR⁴²)R⁴³, —C(═NR⁴²)R⁴³, —C (═NR⁴²)N³⁷R⁴³, NR³⁷C(═NR⁴²)NR³⁷R⁴³,    —C(O)R⁴², —CO₂R⁴², —C(O)(heterocyclyl), —C (O)(C₆-C₁₀aryl),    —C(O)(heteroaryl), —Y—(C₆-C₁₀ aryl), —Y-(heteroaryl), —Y-(5-10    membered heterocyclic), —NR^(6a)R^(6b), —NR^(6a)SO₂R^(6b),    —NR^(6a)C(O)R^(6b), —OC(O)R^(6b), —NR ^(6a)C(O)OR^(6b),    —OC(O)NR^(6a)R^(6b), —OR^(6a), —SR^(6a), —S(O)R^(6a), —SO₂R^(6a),    —SO₃R^(6a), —SO₂NR^(6a)R^(6b), —SO ₂NR⁴²R⁴³, —COR^(6a), —CO₂R^(6a),    —CONR^(6a)R^(6b), —(C₁-C₄)fluoroalkyl, —(C₁-C₄)fluoroalkoxy, —(C    Z³Z⁴)_(a)CN, wherein n is an integer ranging from 0 to 6, and the    aforementioned E¹ groups other than —H and halogen are optionally    substituted by 1 to 5 independently selected R³⁸, or E¹ is selected    from a moiety selected from the group consisting of —(CZ    ³Z₄)_(a)-aryl, —(CZ³Z⁴)_(a)-heterocycle, (C₂-C₆)alkynyl,    —(CZ³Z⁴)_(a)—(C₃-C₆)cycloalkyl, —(CZ³Z⁴)_(a)—(C₅-C₆)cycloalkenyl,    (C₂-C₆) alkenyl and (C₁-C₆)alkyl, which is optionally substituted    with 1 to 3 independently selected Y² groups, where a is 0, 1, 2, or    3, and wherein when a is 2 or 3, the CZ³Z⁴ units may be the same or    different; wherein-   each R³⁸ is independently selected from halo, cyano, nitro,    trifluoromethoxy, trifluoromethyl, azido, —C(O)R⁴⁰, —C(O)OR⁴⁰,    —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —NR ³⁶R³⁹, —OR³⁷,    —SO₂NR³⁶R³⁹, C₁-C₆ alkyl, —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(C₅-C₁₀ heteroaryl), —(CH    ₂)_(n)(5-10 membered heterocyclyl); —C(O)(CH₂)_(n)(C₆-C₁₀ aryl),    —(CH₂)_(n)O(CH₂)_(j)(C₆-C₁₀ aryl), —(CH₂)_(n)O(CH₂)_(i)(5-10    membered heterocyclyl), —C(O)(CH₂)_(n)(5-10 membered heterocyclyl),    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH ₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹, —(CH    ₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰,    —(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH    ₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl), —S    O₂(CH₂)_(n)(5-10 membered heterocyclyl), —(CH₂)_(n)NR³⁶R³⁹, —NR³⁷    SO₂NR³⁶R³⁹, SO₂R³⁶, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl and C₁-C₆    alkylamino, wherein j is an integer ranging from 0 to 2, n is an    integer ranging from 0 to 6, i is an integer ranging from 0 to 6,    the —(CH ₂)_(i)— and —(CH₂)_(n)— moieties of the foregoing R³⁸    groups optionally include a carbon-carbon double or triple bond    where n is an integer between 2 and 6, and the alkyl, aryl,    heteroaryl and heterocyclyl moieties of the foregoing R³⁸ groups are    optionally substituted by one or more substituents independently    selected from halo, cyano, nitro, trifluoromethyl, azido, —OH,    —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR ³⁶C(O)R³⁹,    —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl,    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 membered heterocyclyl),    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and —(CH₂)_(n)OR³⁷, wherein n is an    integer ranging from 0 to 6 and i is an integer ranging from 2 to 6;-   each R⁴² and R⁴³ is independently selected from the group consisting    of H, C₁-C₆ alkyl, C₁-C₆ heteroalkyl, —Y—(C₃-C₁₀ cycloalkyl),    —Y—(C₆-C₁₀ aryl), —Y—(C₆-C₁₀ heteroaryl), —Y— (5-10 membered    heterocyclic), —Y—O—Y—OR³⁷, —Y¹—CO₂—R³⁷, and —Y—OR³⁷, wherein the    alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl and heterocyclic    moieties of the foregoing R⁴² and R⁴³ groups are optionally    substituted by I or more substituents independently selected from    R⁴⁴, wherein-   Y is a bond or is —(C(R³⁷)(H))_(n),-   n is an integer ranging from 1 to 6, and-   Y¹ is —(C(R³⁷)(H))_(n), or-   R⁴² and R⁴³ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted by 1 to 5 R⁴⁴    substituents, with the proviso that R⁴² and R⁴³ are not both bonded    to the nitrogen directly through an oxygen;-   each R⁴⁴ is independently selected from the group consisting of    halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido,    —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶    R³⁹, —NR³⁶R³⁹, —OR³⁷, —SO₂NR³⁶ R³⁹, —SO₂R³⁶, —NR³⁶SO₂R³⁹, —NR    ³⁶SO₂NR³⁷R⁴¹, C1-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₀    cycloalkyl, —C₁-C₆ alkylamino, —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,    —(CH₂)_(n)O(CH₂)_(i)OR³⁷, —(CH₂)_(n)OR³⁷, —S(O)_(j)(C₁-C₆ alkyl),    —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 membered heterocyclic),    —C(O)(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)O(CH₂)j(C₆-C₁₀ aryl),    —(CH₂)_(n)O(CH₂)_(i)(5 to 10 membered heterocyclic), —C    (O)(CH₂)_(n)(5 to 10 membered heterocyclic),    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH ₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹,    —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰, —(CH    ₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(j)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl), —(CH    ₂)_(j)NR³⁹(CH₂)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl), and —SO₂(CH₂)_(n)(5    to 10 membered heterocyclic) wherein, j is an integer from 0 to 2, n    is an integer from 0 to 6 and i is an integer ranging from 2 to 6,    the —(CH₂)_(i)— and —(CH₂)_(n1)— moieties of the foregoing R⁴⁴    groups optionally include a carbon-carbon double or triple bond    wherein n is an integer from 2 to 6, and the alkyl, aryl and    heterocyclic moieties of the foregoing R⁴⁴ groups are optionally    substituted by 1 or more substituents independently selected from    the group consisting of halo, cyano, nitro, trifluoromethyl, azido,    —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —O C(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹,    —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, —SO₂R³⁶, —SO₂NR³⁶R³⁹, C₁-C₆ alkyl,    C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5 to 10    membered heterocyclic), —(CH ₂)_(n)O(CH₂)_(i)OR³⁷ and    —(CH₂)_(n)OR³⁷, wherein n is an integer from 0 to 6 and i is an    integer from 2 to 6; and-   each R⁴⁰ is independently selected from H, C₁-C₁₀ alkyl,    —(CH₂)_(n)(C₆-C₁₀ aryl), C₃-C₁₀ cycloalkyl, and —(CH₂)_(n)(5-10    membered heterocyclic), wherein n is an integer ranging from 0 to 6;-   each R³⁶ and R³⁹ is independently selected from the group consisting    of H, —OH, C₁-C₆ alkyl, C₃-C ₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl),    —(CH₂)_(n)(5-10 membered heterocyclic), —(CH ₂)_(n)O(CH₂)_(i)OR³⁷,    —(CH₂)_(n)CN(CH₂)_(n)OR³⁷, —(CH₂)_(n)CN(CH₂)_(n)R³⁷, and    —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i is    an integer ranging from 2 to 6, and the alkyl, aryl and heterocyclic    moieties of the foregoing R³⁶ and R³⁹ groups are optionally    substituted by one or more substituents independently selected from    —OH, halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁴⁰,    —C(O)OR⁴⁰, —CO(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁷C(O)R⁴¹, —C(O)NR³⁷R⁴¹,    —NR³⁷R⁴¹, —C₁-C₆ alkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5 to 10    membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i)OR³⁷, and    —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6 and i is    an integer ranging from 2 to 6, with the proviso that when R³⁶ and    R³⁹ are both attached to the same nitrogen, then R³⁶ and R³⁹ are not    both bonded to the nitrogen directly through an oxygen;-   each R³⁷ and R⁴¹ is independently selected from the group consisting    of H, OR³⁶, C₁-C₆ alkyl and C₃-C₁₀ cycloalkyl;-   each R^(6a) and R^(6b) is independently selected from the group    consisting of hydrogen, —(CZ⁵Z⁶)_(u)—(C₃-C₆)cycloalkyl,    —(CZ⁵Z⁶)_(u)—(C₅-C₆)cycloalkenyl, —(CZ⁵Z⁶)_(u)-aryl,    —(CZ⁵Z⁶)_(u)-heterocycle, (C₂-C₆)alkenyl, and (C₁-C₆)alkyl, which is    optionally substituted with 1 to 3 independently selected Y³ groups,    where u is 0, 1, 2, or 3, and wherein when u is 2 or 3, the CZ⁵Z⁶    units may be the same or different, or-   R^(6a) and R^(6b) taken together with adjacent atoms can form a    heterocycle;-   each Z³, Z⁴, Z⁵ and Z⁶ is independently selected from the group    consisting of H, F and (C₁-C₆)alkyl, or-   each Z³ and Z⁴, or Z⁵ and Z⁶ are selected together to form a    carbocycle, or-   two Z³ groups on adjacent carbon atoms are selected together to    optionally form a carbocycle;-   each Y² and Y³ is independently selected from the group consisting    of halogen, cyano, nitro, tetrazolyl, guanidino, amidino,    methylguanidino, azido, —C(O)Z⁷, —OC(O)NH₂, —OC(O) NHZ⁷,    —OC(O)NZ⁷Z⁸, —NHC(O)Z⁷, —NHC(O)NH₂, —NHC(O)NHZ⁷, —NHC(O)NZ⁷Z⁸, —C    (O)OH, —C(O)OZ⁷, —C(O)NH₂, —C(O)NHZ⁷, —C(O)NZ⁷Z⁸, —P(O)₃H₂,    —P(O)₃(Z⁷)₂, —S(O)₃H, —S(O)Z⁷, —S(O)₂Z⁷, —S(O)₃Z⁷, —Z⁷, —OZ⁷, —OH,    —NH₂, —NHZ⁷, —NZ⁷Z⁸, —C(═NH)NH₂, —C (═NOH)NH₂, —N-morpholino,    (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₁-C₆)haloalkyl, (C₂-C₆)    haloalkenyl, (C₂-C₆)haloalkynyl, (C₁-C₆)haloalkoxy,    —(CZ⁹Z¹⁰)_(r)NH₂, —(CZ⁹Z¹⁰)_(r)NHZ³, —(CZ⁹Z¹⁰)_(r)NZ⁷Z⁸,    —X⁶(CZ⁹Z¹⁰)_(r)—(C₃-C₈)cycloalkyl, —X    ⁶(CZ⁹Z¹⁰)_(r)—(C₅-C₈)cycloalkenyl, —X⁶(CZ⁹Z¹⁰)_(r)-aryl and    —X⁶(CZ⁹Z¹⁰)_(r)-heterocycle, wherein-   r is 1, 2, 3 or 4;-   X⁶ is selected from the group consisting of O, S, NH, —C(O)—,    —C(O)NH—, —C(O)O—, —S(O)—, —S(O)2— and —S(O)₃—;-   Z⁷ and Z⁸ are independently selected from the group consisting of an    alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12 carbon atoms,    an alkynyl of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8 carbon    atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14    carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7    to 15 carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or-   Z⁷ and Z⁸ together may optionally form a heterocycle;-   Z⁹ and Z¹⁰ are independently selected from the group consisting of    H, F, a (C₁-C₁₂)alkyl, a (C₆-C₁₄)aryl, a (C₅-C₁₄)heteroaryl, a    (C₇-C₁₅)aralkyl and a (C₅-C₁₄)heteroaralkyl, or-   Z⁹ and Z¹⁰ are taken together form a carbocycle, or-   two Z⁹ groups on adjacent carbon atoms are taken together to form a    carbocycle; or-   any two Y² or Y³ groups attached to adjacent carbon atoms may be    taken together to be —O [C(Z⁹)(Z¹⁰)]_(r)O or —O[C(Z⁹)(Z¹⁰)]_(r+1),    or-   any two Y² or Y³ groups attached to the same or adjacent carbon    atoms may be selected together to form a carbocycle or heterocycle;    and wherein-   any of the above-mentioned substituents comprising a CH₃ (methyl),    CH₂ (methylene), or CH (methine) group which is not attached to a    halogen, SO or SO₂ group or to a N, O or S atom optionally bears on    said group a substituent selected from hydroxy, halogen,    (C₁-C₄)alkyl, (C₁-C₄)alkoxy and an —N[(C₁-C₄)alkyl][(C₁-C₄) alkyl];-   E² is —C≡CH or —C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶;-   R⁴⁵ is independently selected from the group consisting of H, a    (C₁-C₆)alkyl and a (C₃-C₈)cycloalkyl;-   R⁴⁶ is selected from the group consisting of heterocyclyl,    —N(R⁴⁷)—C(O)—N(R⁴⁷)(R⁴⁸), —N(R⁴⁷)—C (S)—N(R⁴⁷)(R⁴⁸),    —N(R⁴⁷)—C(O)—OR⁴⁸, —N(R⁴⁷)—C(O)—(CH₂)_(n)—R⁴⁸, —N(R⁴⁷)—SO₂R⁴⁷, —(CH    ₂)_(n)NR⁴⁷R⁴⁸, —(CH₂)_(n)OR⁴⁸, —(CH₂)_(n)SR⁴⁹, —(CH₂)_(n)S(O)R⁴⁹,    —(CH₂)_(n)S(O)₂R⁴⁹, —OC(O)R⁴⁹, —OC(O)OR⁴⁹, —C(O)NR⁴⁷R⁴⁸, heteroaryl    optionally substituted with one or more substituents selected from    the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, and aryl    optionally substituted with one or more substituents selected from    the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹;-   R⁴⁷ and R⁴⁸ are independently selected from the group consisting of    H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, heterocyclyl, —(CH₂)_(n)NR⁵⁰R⁵¹,    —(CH₂)_(n)OR⁵⁰, —(CH₂)_(n)C(O)R⁴⁹, —C(O)₂R⁴⁹, —(CH ₂)_(n)SR⁴⁹,    —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, —(CH₂)_(n)R⁴⁹, —(CH₂)_(n)CN,    aryl optionally substituted with one or more substituents selected    from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl, —(CH    ₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, and heteroaryl    optionally substituted with one or more substituents selected from    the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl,    —(CH₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, or-   R⁴⁷ and R⁴⁸, together with the atom to which they are attached, form    a 3-8 membered ring;-   R⁴⁹ is selected from the group consisting of (C₁-C₆)alkyl,    (C₃-C₈)cycloalkyl, heterocyclyl(C₁-C₆)alkylene, aryl(C₁-C₆)alkylene    wherein the aryl is optionally substituted with one or more    substituents selected from the group consisting of halo, —CF₃,    (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and    —(CH₂)_(n)NR⁵⁰R⁵¹ heteroaryl(C₁-C₆)alkylene wherein the heteroaryl    is optionally substituted with one or more substituents selected    from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,    (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, aryl optionally    substituted with one or more substituents selected from the group    consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN,    —SO₂R⁵⁰ and —(CH ₂)_(n)NR⁵⁰R⁵¹, and heteroaryl optionally    substituted with one or more substituents selected from the group    consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN,    —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹;-   R⁵⁰ and R⁵¹ are independently selected from the group consisting of    H, (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl and —C(O)R⁴⁵, or-   R⁵⁰ and R⁵¹, together with the atom to which they are attached, form    a 3-8 membered ring; and-   E³ is the group defined by -(Z¹¹)-(Z¹²)_(m)-(Z¹³)_(m1), wherein-   Z¹¹ is heterocyclyl or heterocyclylene;-   Z¹² is selected from the group consisting of OC(O), OC(S) and C(O);-   Z¹³ is selected from the group consisting of heterocyclyl, aralkyl,    N(H)R⁵², (C₁-C₃)alkyl, —OR⁵², halo, S(O)₂R⁵⁶, (C₁-C₃)hydroxyalkyl    and (C₁-C₃)haloalkyl;-   m is 0 or 1;-   m1 is 0 or 1;-   R⁵² is selected from the group consisting of H, —(CH₂)_(q)S(O)₂R⁵⁴,    R⁵⁵NR⁵³R⁵³, (C₁-C₃)alkyl, —(CH ₂)_(q)OR⁵³, —C(O)R⁵⁴ and —C(O)OR⁵³;-   q is 0, 1, 2, 3 or 4;-   R⁵³ is (C₁-C₃)alkyl;-   R⁵⁴ is (C₁-C₃)alkyl or N(H)R⁵³;-   R⁵⁵ is (C₁-C₆) alkyl; and-   R⁵⁶ is selected from the group consisting of NH₂, (C₁-C₃)alkyl and    OR⁵².

In a preferred embodiment of the compounds, the compounds arerepresented by the formula B-0:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   Z is O or S;-   X and X¹ are independently selected from the group consisting of H,    C₁-C₆ alkyl, halo, cyano, or nitro, wherein C₁-C₆ alkyl is    optionally substituted;-   R¹, R², R³, R⁴, R⁵ and R⁶ are independently selected from the group    consisting of hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆    alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl are    optionally substituted;-   Q is O, S, NH, N(C₁-C₆ alkyl), or N—Y-(aryl);-   L is N, or CR, wherein R is halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl,    or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆    alkynyl are optionally substituted; and-   R⁷ is selected from the group consisting of H, halogen, C₁-C₆ alkyl,    —C(═O)NR⁹R¹⁰, —C(═O)(aryl), —C(═O)(heterocyclyl),    —C(═O)(heteroaryl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰ and CO₂R⁹, wherein C₁-C₆ alkyl, aryl,    heterocyclyl and heteroaryl are each optionally substituted;-   R⁹ and R¹⁰ are independently selected from the group consisting of    H, C₁-C₆ alkyl, —Y-(cycloalkyl), —Y-(aryl), —Y-(heterocyclyl),    —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹, and —Y—O—R¹¹, wherein    C₁-C₆ alkyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl are each    optionally substituted, or-   R⁹ and R¹⁰ are taken together with the nitrogen to which they are    attached to form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted;-   R⁸ is selected from the group consisting of H, halo and C₁-C₆ alkyl,    wherein C₁-C₆ alkyl is optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y¹ is —(C(R¹¹)(H))_(t)—, and-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted.

In a preferred embodiment of the compounds, X and X¹ are both hydrogen.

In a preferred embodiment of the compounds, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds, R¹ is fluorine.

In a preferred embodiment of the compounds, R⁴ is hydrogen or halogen.

In a preferred embodiment of the compounds R⁴ is fluorine.

In a preferred embodiment of the compounds, R², R³, R⁵, and R⁶ are eachhydrogen.

In a preferred embodiment of the compounds, Q is S, N(C₁-C₆ alkyl), orN—Y-(aryl).

In a preferred embodiment of the compounds, L is CH or N.

In a preferred embodiment of the compounds, R⁸ is selected from thegroup consisting of H, halo and C₁-C₆ alkyl, wherein C₁-C₆ alkyl isoptionally substituted with OH or NR¹⁴R¹⁵, where R¹⁴ and R¹⁵ areindependently H or C₁-C₆ alkyl, or R¹⁴ and R¹⁵ are taken together withthe nitrogen to which they are attached to form a C₅-C₉ heterocyclylring or a heteroaryl ring, wherein said ring is optionally substituted.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, halogen, C₁-C₆ alkyl, —CONR⁹R¹⁰, —SO₂NH₂,—SO₂NR⁹R¹⁰, —Y-heterocycle —Y-heteroaryl, —S-aryl, —S—C₁-C₆ alkyl,—SO—C₁-C₆ alkyl and —SO₂—C₁-C₆ alkyl, wherein C₁-C₆ alkyl isunsubstituted or is substituted with one or two of hydroxy or halogen,and the heterocycle, and heteroaryl are unsubstituted or are substitutedwith one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, R⁷is —CONR⁹R¹⁰.

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are independentlyselected from the group consisting of H, C₁-C₆ alkyl, —Y—O—R¹¹,—Y-(heterocycle), —Y¹—CO₂—R¹¹ and —Y-(aryl), wherein C₁-C₆ alkyl isunsubstituted or is substituted with one or two of hydroxy or halogen,and the heterocycle, and aryl are unsubstituted or are substituted withone or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, R⁹ and R¹⁰ are takentogether with the nitrogen to which they are attached to form apyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinylring, wherein said ring is unsubstituted or is substituted with one ortwo of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, R⁷ is selected from thegroup consisting of H, halogen, C₁-C₆ alkyl, —SO₂NR⁹R¹⁰,—C(═O)(heterocyclyl), —Y-(heterocyclyl), —Y-(heteroaryl), —S-aryl,—S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl and —SO₂—C₁-C₆ alkyl, wherein C₁-C₆alkyl is unsubstituted or is substituted with one or two of hydroxy orhalogen, and the heterocyclyl, and heteroaryl are unsubstituted or aresubstituted with one or two of alkoxy, alkyl, or haloalkyl.

In a preferred embodiment of the compounds, Z is sulfur.

In a preferred embodiment of the compounds, the compounds arerepresented by the formula B-1:

and pharmaceutically acceptable salts and complexes thereof, wherein

-   R¹ is selected from the group consisting of hydrogen, halo, C₁-C₆    alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆    alkenyl and C₂-C₆ alkynyl are optionally substituted;-   R⁷ is selected from the group consisting of H, halogen, C₁-C₆ alkyl,    —C(═O)NR₉R₁₀, —C(═O)(aryl), —C(═O)(heterocyclyl),    —C(═O)(heteroaryl), —Y-(aryl), —Y-(heterocyclyl), —Y-(heteroaryl),    —Y—NR⁹R¹⁰, —SO₂NR⁹R¹⁰ and CO₂R⁹, wherein C₁-C₆ alkyl, aryl,    heterocycle and heteroaryl are each independently optionally    substituted;-   R⁹ and R¹⁰ are independently selected from the group consisting of    H, C₁-C₆ alkyl, —Y-(cycloalkyl), —Y-(aryl), —Y-(heterocyclyl),    —Y-(heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹, and —Y—O—R¹¹, wherein    C₁-C₆ alkyl, cycloalkyl, aryl, heterocycle, and heteroaryl are each    optionally substituted, or-   R⁹ and R¹⁰ taken together with the nitrogen to which they are    attached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring,    wherein said ring is optionally substituted;-   Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t is an integer from 1    to 6;-   Y₁ is —(C(R¹¹)(H))_(t)—;-   R¹¹ at each occurrence is independently H or C₁-C₆ alkyl, wherein    C₁-C₆ alkyl is optionally substituted; and-   R¹² is selected from the group consisting of H, C₁-C₆ alkyl and    —Y-(aryl), wherein C₁-C₆ alkyl and aryl are optionally substituted.

In a preferred embodiment of the compounds, R¹ is hydrogen or halogen.

In a preferred embodiment of the compounds, R¹ is fluorine.

In a preferred embodiment of the compounds, R¹² is unsubstituted C₁-C₃alkyl or unsubstituted benzyl.

In a preferred embodiment of the compounds, R⁷ is —C(O)NR⁹R¹⁰.

In a preferred embodiment of the compounds R⁷ is selected from the groupconsisting of

wherein the members of said group are optionally substituted by 1 to 3independently selected R³⁸.

In a preferred embodiment of the compounds R⁷ is selected from the groupconsisting of

wherein the members of said group are optionally substituted with 1 to 3independently selected R³⁸.

In the third aspect, the invention provides a composition comprising acompound or as depicted in any of the tables and examples hereintogether with a pharmaceutically acceptable excipient.

The fourth aspect of the invention provides a method of inhibiting VEGFreceptor signaling and HGF receptor signaling, the method comprisingcontacting the receptor with a compound or as depicted in any of thetables herein, or with a composition. Inhibition of VEGF and HGFactivity can be in a cell or a multicellular organism. If in amulticellular organism, the method according to this aspect of theinvention comprises administering to the organism a compound or asdepicted in any of the tables herein, or a composition. Preferably theorganism is a mammal, more preferably a human.

The data presented herein demonstrate the inhibitory effects of the VEGFand HGF inhibitors of the invention. These data lead one to reasonablyexpect that the compounds of the invention are useful not only forinhibition of VEGF receptor signaling and HGF receptor signaling, butalso as therapeutic agents for the treatment of proliferative diseases,including cancer and tumor growth.

Preferred compounds according to the invention include those describedin the examples below. Compounds were named using Chemdraw Ultra version6.0.2 or version 8.0.3, which are available through Cambridgesoft.com,100 Cambridge Park Drive, Cambridge, Mass. 02140, Namepro version 5.09,which is available from ACD labs, 90 Adelaide Street West, Toronto,Ontario, M5H, 3V9, Canada, or were derived therefrom.

Synthetic Schemes and Experimental Procedures

The compounds of the invention can be prepared according to the reactionschemes or the examples illustrated below utilizing methods known to oneof ordinary skill in the art. These schemes serve to exemplify someprocedures that can be used to make the compounds of the invention. Oneskilled in the art will recognize that other general syntheticprocedures may be used. The compounds of the invention can be preparedfrom starting components that are commercially available. Any kind ofsubstitutions can be made to the starting components to obtain thecompounds of the invention according to procedures that are well knownto those skilled in the art.

I. SYNTHESIS (GENERAL SCHEMES)

Thieno[3,2-b]pyridine based compounds of formula A-0 may be preparedaccording to the procedures illustrated in the scheme A. Thus,thieno[3,2-b]pyridine-7-ol (I) upon treatment with POCl₃ is converted tothe chloride II. Treatment of this material with a strong base such asn-BuLi followed by an addition of carbon dioxide affords the carboxylateIII which is used without purification in the next step, providing theacyl chloride IV (presumably as a hydrochloride salt) upon its reactionwith oxalyl chloride. The acyl chloride IV is used for the next stepwithout further purification as well: upon its reaction with differentprimary and secondary amines the compound IV is converted to a varietyof primary and secondary amides V which can further be derivatized via asubstitution of the chlorine atom in the pyridine ring.

Thus, V reacting with substituted 4-nitrophenols in a high boiling pointsolvent, such as diphenyl ether in the presence of a base such aspotassium carbonate, produced the nitro derivatives VI which then arereduced to the amines VII upon treatment with a mixture NiCl₂/NaBH₄ (orother conventional reagents). The amines VII also may be used for thenext step without further purification, and upon treatment with2-phenylacetyl isothiocyanates afford phenylacetylthioureas VIII bearingthe amido-substituents such as the ones shown in the scheme A.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings)are independently selected from halo, C₁-C₆alkyl, C₁-C₆ alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆ alkylamino

Thieno[3,2-d]pyrimidine based compounds of formula A-0 may be preparedaccording to the procedures illustrated in the scheme B. Thus,thieno[3,2-d]pyrimidine-7-ol (IX) upon treatment with POCl₃ is convertedto the chloride X. Treatment of this material with a strong base such aslithium tetramethylpiperidide (LiTMP) generated in situ followed by anaddition of carbon dioxide affords the carboxylate XI which is usedwithout purification in the next step, providing the acyl chloride XII(presumably as a hydrochloride salt) upon its reaction with oxalylchloride. The acyl chloride XII reacting with different primary andsecondary amines is converted to a variety of primary and secondaryamides XIII which can further be derivatized via a substitution of thechlorine atom in the pyrimidine ring.

Thus, XIII reacting with substituted 4-nitrophenols in a high boilingpoint solvent, such as diphenyl ether in the presence of a base such aspotassium carbonate, produce the nitro derivatives XIV which are thenreduced to the amines XV upon treatment with a mixture NiCl_(2/)NaBH₄(or other conventional reagents). The amines XV upon treatment with2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XVIbearing the amido-substituents such as the ones shown in the scheme B.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings) are independently selected from halo, C₁-C₆alkyl, C₁-C₆ alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆ alkylamino

Thieno[3,2-b]pyridine based phenylacetylureas of formula A-0 bearingheteroaryl substituents instead of the amido moieties may be preparedaccording to the procedures illustrated in the scheme C. Thus, treatmentof the chloride II with a strong base such as n-BuLi followed by anaddition of trimethyltin (or tributyltin) chloride affords thetrimethylstannyl (or tributylstannyl) derivative XVII. This materialreacting with different heteroaryl bromides in the presence of aPd-catalyst (Stille coupling reaction or similar type reactions)produces heteroaryl-substituted thienopyridines XVIII which can furtherbe derivatized via a substitution of the chlorine atom in the pyridinering.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings) are independently selected from halo, C₁-C₆alkyl, C₁-C₆ alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆ alkylamino

Thus, XVIII reacting with substituted 4-nitrophenols in a high boilingpoint solvent, such as diphenyl ether in the presence of a base such aspotassium carbonate, produced the nitro derivatives XIX which are thenreduced to the amines XX upon treatment with a mixture NiCl₂/NaBH₄ (orother conventional reagents). The amines XX could be used for the nextstep without further purification, and upon treatment with2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXIbearing the heteroaryl substituents such as the ones shown in the schemeC. Heteroaryls shown in the scheme B, in turn may bear additionalsubstituents exemplified (but not limited to) alkyls, amines,alkylamino, aminoalkyls, alkoxyalkyls, hydroxyalkyls,alkylsulfonylalkyls, etc.—known in the art as solubilizingfunctionalities.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings)are independently selected from halo, C₁-C₆alkyl, C₁-C₆ alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆ alkylamino

Pyrrolo[2,3-d]pyrimidine based compounds of formula B-0 may be preparedaccording to the procedures illustrated in the scheme D. Treatment ofthe 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (XXII) with an alkyl halide inthe presence of a base such as sodium hydride affords the alkylatedchlorides XXIII, which reacting with substituted 4-nitrophenols in ahigh boiling point solvent, such as diphenyl ether in the presence of abase such as cesium carbonate, produced the nitro derivatives XXIVreduced to the amines XXV upon hydrogenation (or treatment withconventional reducing agents). The amines XXV reacting with2-phenylacetyl isothiocyanates afford the phenylacetylthioureas XXVIbearing the alkyl substituents such as the ones shown in the scheme D.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings) are independently selected from halo,C₁-C₆alkyl, C₁-C₆alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆alkylamino

Thieno[3,2-b]pyridine based phenylacetylureas of formula A-0 bearingaryl substituents may be prepared according to the proceduresillustrated in the scheme E. Thus vhloride II upon lithiation andsubsequent bromination is converted to the bromide XXVII that reactingwith substituted 4-nitrophenols produces more elaborated compoundXXVIII. This material can be used for Suzuki type (and like) reactionswith a variety of aryl boronic acids (or boronates), in particular withthe ones functionalized with basic groups, thus providing compoundsXXIX. Reduction of XXIX with a mixture NiCl₂/NaBH₄ (or otherconventional reagents) affords amines XXX. The latter upon treatmentwith 2-phenylacetyl isothiocyanates afford the phenylacetylthioureasXXXI bearing aryl substituents such as the ones shown in the scheme E.

Substituents X and Y (up to three, same or different in each of theindicated benzene rings) are independently selected from halo,C₁-C₆alkyl, C₁-C₆alkoxy, cyano, nitro, hydroxy, amino, C₁-C₆alkylamino

Bromides XXVIII also can be used for Suzuki type (and like) reactionswith a variety of hydroxyphenyl boronic acids (boronates), to formphenolic compounds XXXII. These phenols reacting with different alcohols(Mitsunobu reaction), in particular functionalized with basic groups,provide compounds XXXIII. Reduction of XXXIII with a mixture NiCl₂/NaBH₄(or other conventional reagents) affords amines XXXIV which upontreatment with 2-phenylacetyl isothiocyanates afford thephenylacetylthioureas XXXV bearing the aryl substituents such as theones shown in the scheme F.

II. SPECIFIC EXAMPLES

Example 11-(4-(2-(Dimethylcarbamoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(8a) Step 1: 7-Chlorothieno[3,2-b]pyridine (2)

A stirred suspension of thieno[3,2-b]pyridin-7-ol (1, 5.0 g, 33.1 mmol)in POCl₃ (15 mL) was heated to 105° C. in an oil bath for 4 hrs. Theresultant solution was cooled to room temperature and the POCl₃ wasremoved under reduced pressure. The residue was cooled in an ice/waterbath and cold water was added. The water was made basic withconcentrated NH₄OH solution and extracted with EtOAc. The organicextract was dried over anhydrous sodium sulfate and concentrated toproduce an oil which was purified by column chromatography (eluentEtOAc-hexane, 1:4) to afford the title compound as a brown solid (4.5 g,72% yield). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.60 (d, J=4.9 Hz, 1H),7.80 (d, J=5.5 Hz, 1H), 7.60 (d, J=5.5 Hz, 1H), 7.30 (d, J=4.9 Hz, 1H).

Steps 2-4: 7-Chloro-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide (5)

To a stirred solution of 2 (3.0 g, 17.8 mmol) in dry THF (60 mL) at −78°C. was added n-BuLi (7.8 mL, 19.6 mmol, 2.5 M solution in hexanes) andthe resultant suspension was stirred for 15 minutes. Solid carbondioxide (excess) was added and the mixture was allowed to warm to roomtemperature over a period of 1 hour. The solvent was removed underreduced pressure and the resultant lithium carboxylate 3 was usedwithout further purification (3.88 g, quantitative).

To a stirred suspension of 3 (3.5 g, 15.9 mmol) in dry DCM (50 mL) wasadded (COCl)₂ (3.96 g, 31.2 mmol) and dry DMF (1 drop). The reactionmixture was heated to reflux for 2 hrs. The solvents were evaporated toproduce 4 (presumably as an HCl salt) which was used directly in thenext step.

Acyl chloride 4 (2.42 g, 10.5 mmol) was suspended in dry DCM (105 mL) at0° C. and Me₂NH (15.7 mL, 2M solution in THF, 31.4 mmol) was added andthe reaction mixture was stirred overnight. The solvent was removed andthe residue was dissolved in EtOAc and washed with water. The organicphase was collected and dried over anhydrous sodium sulfate thenfiltered and concentrated under reduced pressure to produce a residue,which was purified by column chromatography (eluent EtOAc-hexane, 9:1)to afford 5 as a yellow solid (1.65 g, 45% yield). ¹H NMR (400 MHz,CDCl₃) δ (ppm): 8.62 (d, J=4.8 Hz, 1H), 7.76 (s, 1H), 7.37 (d, J=4.8 Hz,1H), 3.35-3.25 (m, 3H), 3.25-3.20 (m, 3H).

Step 5:7-(2-Fluoro-4-nitrophenoxy)-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide(6)

A mixture of 5 (1.65 g, 6.85 mmol), potassium carbonate (5.68 g, 41.1mmol) and 2-fluoro-4-nitrophenol (1.65 g, 10.3 mmol) were heated to 170°C. in diphenyl ether (20 mL) for 5 hrs. The mixture was cooled to roomtemperature, diluted with EtOAc and washed with water. The organic phasewas collected, dried over anhydrous sodium sulfate and the solvents wereremoved under reduced pressure. The residue was purified by columnchromatography (eluents EtOAc-hexane 9:1, then MeOH-EtOAc 1:4) to afford6 as a yellow solid (1.02 g, 41% yield).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.64 (d, J=5.3 Hz, 1H), 8.46 (dd,J=2.8 and 10.3 Hz, 1H), 8.20 (ddd, J=1.3 and 2.6 and 9.0 Hz, 1H), 7.98(s, 1H), 7.73 (dd, J=8.3 Hz, 1H), 6.99 (dd, J=0.9 and 4.8 Hz, 1H),3.25-3.30 (m, 3H), 3.02-3.11 (m, 3H).

Steps 6-7:1-(4-(2-(Dimethylcarbamoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(8a)

To a solution of 6 (190 mg, 0.55 mmol) in MeOH (10 mL) at 0° C. wasadded NiCl₂×6H₂O (241 mg, 1.02 mmol) and NaBH₄ (81.4 mg, 2.2 mmol). Thereaction mixture was stirred for 1 hr, concentrated to dryness and theresultant solid was dissolved in 1 M HCl. The aqueous solution was thenmade basic with concentrated NH₄OH solution and extracted with EtOAc.The organic phase was collected, dried over anhydrous sodium sulfate andfiltered. The solvent was evaporated under reduced pressure and theresultant solid was triturated with diethyl ether to afford 7 as a whitesolid that was used immediately in the next step.

To a suspension of 7 (465.8 mg, 1.41 mmol) in THF (20 mL) was addedbenzyl isothiocyanate (374 mg, 2.12 mmol) and the reaction mixture wasstirred for 1 hr, concentrated under reduced pressure and the resultantresidue was purified by column chromatography (eluent EtOAc-MeOH 19:1)to afford a yellow solid which was triturated with Et₂O to afford 8a asan off-white solid (534 mg, 75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.47 (s, 1H), 11.78 (s, 1H), 8.57 (d, J=4.2 Hz, 1H), 8.05-7.95(m, 1H), 7.93 (s, 1H), 7.52 (s, 2H), 7.33 (d, J=3.9 Hz, 1H), 7.28-7.23(m, 1H), 6.72 (d, J=5.3 Hz, 1H), 3.83 (s, 2H), 3.26 (s broad, 3H), 3.05(s broad, 3H).

Examples 2-11

Examples 2-11 (compounds 8b-k) were prepared using the same proceduresas described for the compound 8a, example 1 (scheme 1). Characterizationof 8b-k is provided in table 1.

TABLE 1

8b-k: Examples 2-11 Characterization of compounds 8b-k (examples 2-11)Cpd Ex R Name Characterization 8b 2

1-(4-(2-(2- morpholinoethylcarba moyl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆).δ.ppm: 12.52 (s, 1H), 11.85 (s, 1H), 8.96 (t, J = 5.3 Hz, 1H), 8.62 (d,J = 5.5 Hz, 1H), 8.28 (s, 1H), 8.06 (d, J = 10.9 Hz, 1H), 7.57 (d, J =6.5 Hz, 2H), 7.38-7.30 (m, 5H), 6.77 (d, J = 5.2 Hz, 1H), 3.86 (s, 2H),3.61 (t, J=4.4 Hz, 4H), 3.46 (q, J = 6.6 Hz, 2H), 3.39- 3.36 (m, 6H). 8c3

1-(4-(2- (morpholinoethylcarba moyl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆).δ.ppm: 12.52 (s, 1H), 8.72 (s, 1H), 8.54 (d, J = 6.1 Hz, 1H), 8.0-7.98(m, 2H), 7.38-7.26 (m, 7H), 6.73 (d, J = 5.7 Hz, 1H), 3.72 (s, 8H), 2.02(s, 2H). 8d 4

1-(4-(2-(3,4- dimethoxyphenylcarb amoyl)thieno[3,2-b]pyridin-7-yloxy)-3- fluorophenyl)-3-(2- phenylacetyl)thiourea ¹ H NMR(400 MHz, DMSO-d₆). δ.ppm: 10.64 (s, 1H), 8.61 (d, J = 5.4 Hz, 1H), 8.51(s, 1H), 8.03 (d, J = 12.7 Hz, 1H), 7.92 (s, 1H), 7.54 (m, 2H), 7.44 (d,J = 2.4 Hz, 1H), 7.29 (m, 7H), 6.96 (d, J = 8.8 Hz, 1H), 6.76 (d, J =6.1 Hz, 1H), 3.82 (s, 2H), 3.76 (d, J = 8.3 Hz, 6H). 8e 5

1-(4-(2- (methylcarbamoyl) thieno[3,2-b]pyridin-7- yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆).δ.ppm: 12.47 (s, 1H), 11.80 (s, 1H), 8.92 (s, 1H), 8.55 (d, J = 3.7 Hz,1H), 8.18 (s, 1H), 8.01 (d,.J = 11.9 Hz, 1H), 7.52 (s, 2H), 7.32 (s,4H), 7.25 (s, 1H), 6.71 (d, J = 4.9 Hz, 1H), 3.81 (s, 2H), 2.83 (d, J =3.3 Hz, 3H). 8f 6

1-(4-(2-(3,4- dimethoxyphenethyl carbamoyl)thieno[3,2-b]pyridin-7-yloxy)-3- fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR(400 MHz, DMSO-d₆). δ.ppm: 12.47 (s, 1H), 11.81 (s, 1H), 9.03 (t, J =5.7 Hz, 1H), 8.56 (d, J = 5.5 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J = 11.4Hz, 1H), 7.53 (s, 2H), 7.33 (m, 4H), 7.27 (m, 1H), 6.84 (m, 2H), 6.73(m, 2H), 3.82 (s, 2H), 3.70 (d, J = 4.5 Hz, 6H), 3.50 (q, J = 6.6 Hz,2H), 2.80 (t, J = 7.0 Hz, 2H). 8g 7

1-(4-(2- (diethylcarbamoyl) thieno[3,2-b]pyridin-7- yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆).δ.ppm: 12.58 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.05-7.92 (m, 2H),7.40 (m, 4H), 7.33 (m, 3H), 6.71 (s, 1H), 3.80 (s, 2H), 3.59 (q, J = 7.2Hz, 4H), 1.29 (m, 6H). 8h 8

1-(4-(2-(4- isopropylphenylcarba moyl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δ.ppm: 12.48 (s, 1H), 11.81 (s, 1H), 10.56 (s, 1H), 8.61 (d J = 5.4 Hz,1H), 8.53 (s, 1H), 8.03 (d, J = 12.3 Hz, 2), 7.66 (d, J = 8.4 Hz, 2H),7.54 (m, 2H), 7.33 (m, 4H), 7.23 (m, 3H), 6.75 (d, J = 5.3 Hz, 1H), 3.82(s, 2H), 2.87 (m, 1H), 1.20 (d, J = 6.8 Hz, 6H). 8i 9

1-(4-(2- carbamoylthieno[3,2- b]pyridin-7-yloxy)-3- fluorophenyl)-3-(2-phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δ. ppm: 12.48 (s, 1H),11.81 (s, 1H), 8.56 (dd, J = 0.6 Hz and 5.5 Hz, 1H), 8.40 (s, 1H), 8.25(d, J = 0.8 Hz, 1H), 8.01 (d, J = 13.3 Hz, 1H), 7.86 (s, 1H), 7.33 (m,4H), 7.25 (m, 1H), 6.72 (d, J = 5.3 Hz, 1H), 3.82 (s, 2H). 8j 10

1-(4-(2-(N-methoxy-N- methylcarbamoyl)thie no[3,2-b]pyridin-7- yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δ.ppm: 12.51 (s, 1H), 11.85 (s, 1H), 8.63 (d, J = 5.3 Hz, 1H), 8.22 (s,1H), 8.04 (d, J = 13.1 Hz, 1H), 7.57 (m, 2H) 7.36 (m, 4H), 7.30 (m, 1H),6.77 (d, J = 5.3 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.39 (s, 3H). 8k11

Methyl 2-(1-(4-(2- (carbamoyl)thieno[3, 2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourei do)propanoate ¹H NMR (400MHz, DMSO-d₆). δ ppm: 12.48 (s, 1H), 11.80 (s, 1H), 9.28 (d, J = 6.9 Hz,1H), 8.59 (d, J = 5.3 Hz, 1H), 8.38 (s, 1H), 8.02 (d, J = 12.9 Hz, 1H),7.53 (m, 2H), 7.33 (m, 4H), 7.28 (m, 1H), 6.75 (d, J = 5.3 Hz, 1H), 4.49(m, 1H), 3.82 (s, 2H), 3.66 (s, 3H), 1.44 (d, J = 7.4 Hz, 3H).

Example 121-(4-(2-(Thiazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(13a) Step 1: 7-Chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine

To a solution of 2 (1.0 g, 5.9 mmol) in dry THF (60 mL) at −78° C. wasadded n-BuLi (2.36 mL, 5.9 mmol, 2.5 M solution in hexanes) and theresultant brown precipitate was stirred for 10 min. Trimethytin chloride(1.18 g, 5.9 mmol) in dry THF (10 mL) was added slowly and the mixturewas allowed to stir at −78° C. for 2 hrs, quenched with methanol at −78°C. and the solvents were removed under reduced pressure. The residue wasdissolved in EtOAc and washed with water; the organic phase wascollected, dried over anhydrous sodium sulfate and filtered. The EtOAcwas evaporated under reduced pressure and the resultant oil was purifiedby column chromatography (eluent EtOAc-hexane 1:4) to afford 9 (1.2 g,63% yield) as a brown solid. ¹H NMR (400 MHz, CDCl₃)

ppm: 8.21 (d, J=5.1 Hz, 1H), 7.36 (s, 1H), 6.91 (m, 1H), 0.16 (s, 9H).

Step 2: 7-Chloro-2-(thiazol-2-yl)thieno[3,2-b]pyridine (10)

To a solution of 9 (175 mg, 0.53 mmol) and 2-bromothiazole (94 mg, 0.58mmol) in dry toluene (6 mL) was added Pd(PPh₃)₄ (62 mg, 0.053 mmol) andthe reaction mixture was refluxed overnight, cooled to room temperatureand the solvents were removed under reduced pressure. The resultantsolid was triturated with hexane/Et₂O and then purified by columnchromatography (eluent EtOAc-hexane 1:1) to give 10 as a white solid (75mg, 56% yield). ¹H NMR (400 MHz, DMSO-d₆)

ppm: 8.65 (d, J=5.1 Hz), 8.2 (s, 1H), 7.97 (s, 2H), 7.61 (d, J=5.1 Hz).

Step 3:7-(2-Fluoro-4-nitrophenoxy)-2-(thiazol-2-yl)thieno[3,2-b]pyridine (11)

To a suspension of 10 (194 mg, 0.77 mmol) in Ph₂O (10 mL) was added2-fluoro-4-nitrophenol (240 mg, 1.53 mmol) and potassium carbonate (425mg, 3.08 mmol) and the reaction mixture was heated at 180° C. for 4 hrs.The reaction mixture was cooled to room temperature and diluted withEtOAc. The resultant solution was washed with water and the organiclayer was collected, dried over anhydrous sodium sulfate and filtered.The solvents were removed under reduced pressure; the residue wasdissolved in DCM, and purified by column chromatography (eluentEtOAc-hexane 4:1) to afford 11 (190 mg, 66% yield) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆)

ppm: 8.61 (d, J=5.5 Hz, 1H), 8.46 (dd, J=2.74 and 10.37 Hz), 8.24 (s,1H), 8.20-8.10 (m, 1H), 7.95 (s, 2H), 7.73 (t, J=8 Hz, 1H), 6.98 (d,J=5.3 Hz, 1H).

Steps 4-5.1-(4-(2-(Thiazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(13a)

To a suspension of 11 (190 mg, 0.55 mmol) in MeOH (10 mL) at 0° C. wasadded NiCl₂.6H₂O (241 mg, 1.02 mmol) and NaBH₄ (81.4 mg, 2.2 mmol). Thereaction mixture was allowed to stir for 1 hr, concentrated to drynessand the resultant solid was dissolved in 1 M HCl. The aqueous solutionwas then made basic with concentrated ammonium hydroxide solutionwhereupon 12 precipitated as a grey solid, which was collected byfiltration and used crude in the next step.

To a suspension of the amine 12 (152 mg, 0.44 mmol) in THF (10 mL) wasadded benzyl isothiocyanate (118 mg, 0.66 mmol) and the reaction mixturewas stirred for 1 hr, concentrated under reduced pressure and purifiedby column chromatography (eluents EtOAc-hexane 3:1, then EtOAc) toafford a yellow solid. Trituration of this material with Et₂O/hexanegave 13a (100 mg, 43% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)

ppm: 12.48 (s, 1H), 11.81 (s, 1H), 8.55 (d, J=5.5 Hz, 1H), 8.19 (s, 1H),8.00 (d, J=13.3 Hz, 1H), 7.95 (d, J=3.1 Hz, 1H), 7.94 (d, J=3.1 Hz, 1H),7.53 (m, 2H), 7.33 (m, 3 H), 7.25 (m, 2H), 6.72 (d, J=5.5 Hz, 1H), 3.82(s, 2H).

Example 13

Examples 13-19 (compounds 13b-h) were prepared using the same proceduresas described for the compound 13a (example 12, scheme 2).Characterization of compounds 13b-h (examples 13-19) is provided intable 2.

TABLE 2

13b-h: examples 13-19 Characterization of compounds 13b-h (examples13-19) Cpd Ex R Name Characterization 13b 13

1-(4-(2-(Pyridin-2- yl)thieno[3,2-b]pyridin-7- yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆). δ ppm: 12.47 (s,1H), 11.81 (s, 1H), 8.61 (d, J = 2.9 Hz, 1H), 8.51 (d, J = 5.5 Hz, 1H),8.36 (s, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.0 (d, J = 17 Hz, 1H), 7.93(dt, J = 1.76 and 7.82 Hz, 1H), 7.51 (m, 2H), 7.32 (m, 4H), 7.26 (m,1H), 6.65 (d, J = 5.5 Hz, 1H),3.82 (s, 2H). MS (m/z) 515.2 (M + H) 13c14

N-(3-Fluoro-4-(2- (pyrimidin-2- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothio yl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆).δ ppm; 12.51 (s, 1H), 11.82 (s, 1H), 8.95 (m, 2H), 8.59 (m, 1H), 8.34(s, 1H), 8.04 (m, 1H), 7.55 (m, 3H), 7.34 (m, 4H), 7.28 (m, 1H), 6.75(m, 1H), 3.82 (s, 2H). MS (m/z) 516.2 (M + H) 13d 15

N-(3-Fluoro-4-(2-(1- methyl-1H-imidazol-2- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothio yl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆).δ ppm; 12.48 (s, 1H), 11.84 (s, 1H), 8.50 (m, 1H), 8.1 (s, 1H), 8.04 (d,J = 12.1 Hz, 1H), 7.63 (s, 1H), 7.56 (m, 2H), 7.39 (s, 1H), 7.33 (m,4H), 7.27 (m, 1H), 7.19 (m, 1H), 6.77 (d, J = 5.7 Hz, 1H). MS (m/z)518.2 (M + H) 13e 16

N-(3-Fluoro-4-(2- (thiophen-2-yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothio yl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆).δ ppm: 12.48 (s, 1H), 11.84 (s, 1H), 8.50 (m, 1H), 8.04 (m, 1H), 7.79,(s, 1H), 7.73 (s, 1H), 7.63 (m, 2H), 7.39 (s, 4H), 7.27 (m, 1H), 7.19(m, 1H), 6.65 (m, 1H), 5.74 (m, 1H), 3.81 (s, 2H). MS (m/z) 520.0 (M +H) 13f 17

N-(4-(2-(1,3,4- Thiadiazol-2- yl)thieno[3,2-b]pyridin-7- yloxy)-3-fluorophenylcarbamothio yl)-2-phenylacetamide ¹H NMR (400 Mhz, DMSO-d₆).δ ppm: 12.47 (s, 1H), 11.82 (s, 1H), 8.57 (d, J = 5.5 Hz, 1H), 8.16 (s,1H), 8.0 (d, J = 13 Hz, 1H), 7.56 (m, IH), 7.36 (m, 4H), 7.26 (m, 2H),6.71 (d, J = 5.3 Hz, 1H), 3.82 (s, 2H). MS (m/z) 522 (M + H) 13g 18

N-(3-fluoro-4-(2-(pyridin- 3-yl)thieno[3,2-b]pyridin-7-yl)-yloxy)phenylcarbamothio yl)-2-phenylacetamide ¹H NMR (400MHz,DMSO-d₆) δ ppm; 12.49 (s, 1H), 11.85 (s, 1H), 9.12 (dd, J = 0.8 and2.3 Hz), 8.63 (dd, J = 1.6 and 4,7 Hz, 1H), 8.55 (d, J = 5.5 Hz, 1H),8.27 (m, 1H), 8.23 (s, 1H), 8.0 (d, J = 13.1 Hz, 1H), 7.54 (m, 3H), 7.32(m, 4H), 7.26 (m, 2H), 6.69 (dd, J = 0.9 and 5.5 Hz, 1H), 3.81 (s, 2H).MS (m/z) 515.2 (M + H) 13h 19

N-(3-fluoro-4-(2-(2- morpholinothiazol-5- yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothio yl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆).δ ppm: 12.45 (s, 1H), 11.81 (s, 1H), 8.44 (dd, J = 1.2, 5.48 Hz, 1H),7.98 (d, J = 12 Hz, 1H), 7.74 (s, 1H), 7.50 (s, 3H), 7.33 (m, 4H), 7.27(m, 2H), 6.59 (d, J = 5.5 Hz, 1H), 3.82 (s, 2H), 3.72 (t, J = 4.7 Hz,4H), 3.47 (t, J = 4.9 Hz,4H). MS (m/z) 606.2 (M + H)

Example 201-(4-(2-(1-Hydroxyethyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(18a) Step 1. 7-Chlorothieno[3,2-b]pyridine-2-carbaldehyde (14)

To a solution of 2 (200 mg, 1.18 mmol) in dry THF (10 mL) at −78° C. wasadded n-BuLi (0.57 mL, 1.42 mmol, 2.5 M solution in hexanes) and theresultant suspension was stirred for 20 min. Dry DMF (0.5 mL, excess)was added and the reaction mixture was stirred for an additional 2 hrs.The reaction mixture was quenched with methanol at −78° C. and water wasadded. The mixture was extracted with EtOAc and the organic extractswere combined, dried over anhydrous sodium sulfate and filtered. Thesolvent was removed under reduced pressure and the resultant yellowsolid was triturated with hexane to afford 14 (250 mg, 100% yield) as apale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 10.2 (s, 1H), 8.78(d, J=5.1 Hz, 1H), 8.61 (s, 1H), 7.78 (d, J=5.1 Hz, 1 H).

Steps 2-3.1-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)ethanol (16)

To a solution of 14 (200 mg, 1 mmol) in dry THF (5 mL) at −78° C. wasadded methylmagnesium bromide (0.51 mL, 1 mmol, 2 M solution in dibutylether) and the reaction mixture was stirred at −78° C. for 1 hr. Thereaction was quenched with water and extracted with EtOAc. The organicphase was dried over anhydrous sodium sulfate and evaporated. Theresultant solid was washed with hexane to give 15 as a white solid (177mg, 83% yield), which was used crude in the next step.

To a suspension of 15 (170 mg, 0.79 mmol) in Ph₂O (10 mL) was added2-fluoro-4-nitrophenol (250 mg, 1.58 mmol) and potassium carbonate (436mg, 3.16 mmol) and the reaction mixture was heated at 180° C. for 4 hrs,cooled to room temperature and diluted with EtOAc. The solution waswashed with water and the organic layer was collected, dried overanhydrous sodium sulfate and filtered. The solvents were removed underreduced pressure. The residue was dissolved in DCM, and purified bycolumn chromatography (eluent EtOAc-hexane, 4:1) to afford 16 (125 mg,47% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d6)

ppm: 8.52 (dd, J=0.8 and 5.5 Hz, 1H), 8.44 (dd, J=2.5 and 10.2 Hz, 1H),8.15 (d, J=10.2 Hz, 1H), 7.63 (t, J=8.2 Hz, 1H), 7.41 (s, 1H), 6.86 (d,J=5.3 Hz, 1H), 5.96 (dd, J=0.4 Hz and 4.9 Hz), 5.09 (m, 1H), 1.49 (d,J=6.5 Hz, 3H).

Steps 4-5.1-(4-(2-(1-Hydroxyethyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(18a)

To a suspension of 16 (129 mg, 0.39 mmol) in MeOH (5 mL) at 0° C. wasadded NiCl₂.6H₂O (183 mg, 0.77 mmol) and sodium borohydride (57 mg, 1.5mmol). The reaction mixture was allowed to stir for 1 hr, concentratedto dryness and the resultant solid was dissolved in 1 M HCl. The aqueoussolution was then made basic with concentrated ammonium hydroxidesolution, extracted with EtOAc and the organic extract was dried overanhydrous sodium sulfate then filtered. The solvent was removed underreduced pressure to give 17 (110 mg, 94% yield) as brown oil, which wasused immediately in the next step.

To an emulsion of 17 (110 mg, 0.36 mmol) in THF (10 mL) was added2-phenylacetyl isothiocyanate (76 mg, 0.43 mmol) and the reactionmixture was stirred for 1 hr, concentrated and the residue was purifiedby column chromatography (eluents EtOAc-hexane 3:1, then EtOAc) toafford a yellow solid which upon trituration with diethyl ether/hexanegave 18a as an off-white solid (90 mg, 52% yield). ¹H NMR (400 MHz,DMSO-d₆)

ppm: 12.47 (s, 1H), 11.81 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.2 (s, 1H),7.9 (d, J=12.3 Hz, 1H), 7.51-7.44 (m, 2H), 7.30 (d, J=0.9 Hz, 1H),7.33-7.31 (m, 3H), 7.30-7.24 (m, 1H), 6.57 (d, J=5.3 Hz, 1H), 5.91 (d,J=4.9 Hz, 1H), 5.09 (m, 1H), 3.9 (s, 2H), 1.49 (d, J=6.3 Hz, 3H).

Example 21

1-(4-(2-(1-Hydroxy-2-methylpropyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(18b)

Title compound was prepared using the same procedures as described forthe compound 18a (example 20, scheme 3). ¹H NMR (400 MHz, DMSO-d₆)

1 ppm: 12.46 (s, 1H), 11.80 (s, 1H), 8.43 (d, J=5.9 Hz, 1H), 7.98 (d,J=2.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.35 (s, 1H), 7.32 (m, 3H), 7.28 (m,1H), 6.55 (d, J=5.5 Hz, 1H), 5.91 (d, J=4.7 Hz, 1H), 4.70 (t, J=5.1 Hz,1H), 3.8 (s, 2H), 1.95 (m, 1H), 0.9 (dd, J=0.7 and 10.2 Hz, 6H).

Example 221-(4-(6-(2-Morpholinoethylcarbamoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(26a) Step 1: 4-Chlorothieno[3,2-d]pyrimidine (20)

To a stirred solution of (COCl)₂ (7.33 mL, 84.11 mmol) in anhydrous(CH₂Cl)₂ (20 mL) at 0° C. under nitrogen was added DMF (4.47 mL, 57.18mmol). After 20 min a solution of thieno[3,2-d]pyrimidin-4(3H)-one (19)(4 g, 26.28 mmol) in anhydrous (CH₂Cl)₂ (5 mL added drop wise to thereaction mixture which was stirred for 20 min at 0° C., warmed to roomtemperature over another 20 min, heated at 80° C. for 1.5 hours, andcooled to room temperature. Finally, the reaction mixture was pouredinto water and extracted with DCM. The extract was washed sequentiallywith water, brine, dried over Na₂SO₄, filtered and evaporated to affordthe title compound 20 (4.36 g, 97% yield) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ(ppm): 9.02 (s, 1H), 8.59 (d, J=5.2 Hz, 1H), 7.75 (d,J=5.2 Hz, 1H).

Step 2: 4-Chlorothieno[3,2-d]pyrimidine-6-carbonyl chloride (22)

To a stirred solution of 2,2,6,6-tetramethylpiperidine (4.45 mL, 26.37mmol) in anhydrous THF (50 mL) at 0° C. under nitrogen was added n-BuLi(10.55 mL, 26.37 mmol, 2.5 M in hexanes). The reaction mixture wasstirred for 30 min, then a solution of 20 (3 g, 17.58 mmol) in anhydrousTHF (10 mL) was added drop wise at −78° C. over 30 min followed by dryice (10 g). The resultant suspension was warmed to the room temperatureover 2 hours and filtered to afford the lithium carboxylate 21 as ayellow solid (4.5 g), which was used for the next step without furtherpurification.

To a stirred solution of (COCl)₂ (2.95 mL, 33.82 mmol) in anhydrous DCM(30 mL) at 0° C. under nitrogen was added DMF (0.5 mL, 6.45 mmol). Thereaction mixture was stirred for 20 min and treated with a solution ofthe carboxylate 21 (3.71 g, 16.89 mmol) in anhydrous DCM (5 mL) (dropwise addition at 0° C.), stirred for additional 10 min and heated at 60°C. for 3 hours, cooled to room temperature and concentrated underreduced pressure to afford the title compound 22 (3.90 g, 99% yield) asa yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 9.02 (s, 1H), 8.59 (d,J=5.2 Hz, 1H), 7.75 (d, J=5.2 Hz, 1H).

Step 3:4-Chloro-N-(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide (23)

To a stirred solution of 22 (500 mg, 2.15 mmol) in anhydrous DCM (20 mL)at 0° C. under nitrogen was added 4-(2-aminoethyl)-morpholine (307 mg,2.36 mmol). The reaction mixture was allowed to warm to the roomtemperature over 3 hours and was stirred for additional 14 hours,treated with saturated aqueous solution of NHCO₃ and extracted with DCM.The organic layer was dried over Na₂SO₄, filtered, and concentrated. Theresidues was purified by flash chromatography on silica gel (eluentsMeOH— DCM, 5:95, then 1:9) to afford the title compound 23 (458 mg, 65%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 9.13 (t, J=5.6Hz, 1H), 9.08 (s, 1H), 8.32 (s, 1H), 3.60-3.54 (m, 4H), 3.44 (q, J=6.8Hz, 2H), 2.54-2.48 (m, 2H), 2.46-2.40 (m, 4H).

Step 4:4-(2-Fluoro-4-nitrophenoxy)-N-(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide(24)

To a stirred solution of compound 23 (458 mg, 1.40 mmol) in Ph₂O (6 mL)was added 2-fluoro-4-nitrophenol (242 mg, 1.54 mmol). The reactionmixture was heated at 120° C. for 2.5 hours, treated with K₂CO₃ (80 mg,0.56 mmol) and heated at the same temperature for additional 18 hours.After cooling, the reaction mixture was purified by flash chromatographyon a silica gel column (eluents EtOAc-hexane 5:95, 1:1, then MeOH-DCM,5:95 and 1:9), to afford the title compound 24 (570 mg, 91% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ(pm): 9.09 (t, J=5.6 Hz, 1H),8.77 (s, 1H), 8.41 (dd, J=2.4 and 10.4 Hz, 1H), 8.30 (s, 1H), 8.22 (dd,J=2.4 and 8.8 Hz, 1H), 7.88 (t, J=8.8 Hz, 1H), 3.60-3.52 (m, 4H), 3.45(q, J=6.8 Hz, 2H), 2.50 (q, J=6.8 Hz, 2H), 2.46-2.40 (m, 4H).

Step 5:4-(4-Amino-2-fluorophenoxy)-N-(2-morpholinoethyl)thieno[3,2-d]pyrimidine-6-carboxamide(25)

To a stirred solution of 24 (1.30 g, 2.72 mmol) in anhydrous MeOH (15mL) at room temperature under nitrogen were added NiCl₂×6H₂O (605 mg,2.54 mmol) and NaBH₄ (192 mg, 5.08 mmol), respectively. The reactionmixture was stirred for 50 min, concentrated, cooled to 0° C., treatedwith HCl (10 mL, 1M) followed by addition of NH₄OH (29%) (pH 9-10), andfinally extracted with AcOEt. The organic extract was successivelywashed with water and brine, dried over Na₂SO₄, filtered, andconcentrated to afford the title compound 25 (450 mg, 85% yield) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ(ppm): 9.04 (t, J=5.6 Hz, 1H),8.73 (s, 1H), 8.23 (s, 1H), 7.07 (t, J=8.8 Hz, 1H), 6.48 (dd, J=2.4 and13.2 Hz, 1H), 6.40 (dd, J=2.4 and 8.8 Hz, 1H), 5.47 (s, 2H), 3.62-3.52(m, 4H), 3.44 (q, J=6.8 Hz, 2H), 2.56-2.48 (m, 2H), 2.46-2.40 (m, 4H).

Step 6:1-(4-(6-(2-Morpholinoethylcarbamoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(26a)

To a stirred solution of 25 (450 mg, 1.07 mmol) in anhydrous THF (10 mL)under nitrogen was slowly added benzyl isothiocyanate (0.5 mL). Thereaction mixture was stirred for 18 hours and concentrated under reducedpressure. The residue was purified by flash chromatography on a silicagel column (eluent MeOH-DCM, 5:95→10:90) followed by reversed phasechromatography purification (column Phenomene X, C18, eluent H₂-MeOH,50:50→5:95, 10 mL/min) to afford the title compound 26a (104 mg, 16%yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ((ppm): 12.43(s,1H), 11.80(s, 1H), 9.07(t, J=5.6 hz, 1H), 8.76(s, 1H), 8.28(s, 1H),7.93(dd, J=2.4 and 12.0 Hz, 1H), 7.54(t, J=8.8 Hz, 1H), 7.48(dd, J=1.2and 8.8 Hz, 1H), 7.39-7.30(m, 4H), 7.30-7.20(m, 1H), 3.82(s, 2H),3.60-3.54(m, 4H), 3.45(q, J=6.4 Hz, 2H), 2.50(m, 2H), 2.48-2.40(m, 4H).

Examples 23-27

Examples 23-27 (compounds 26b-e) were prepared using the same proceduresas described for the compound 26a, example 22 (scheme 4).Characterization of compounds 26b-e (examples 23-27) is provided intable 3.

TABLE 3

26b-e: Examples 23-27 Characterization of compounds 26b-e (examples23-27) Cpd Ex R Name Characterization 26b 23

1-(4-(6- (Dimethylcarbamoyl)th ieno[3,2-d]pyrimidin 4-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.77 (s, 1H), 8.01 (s, 1H), 7.93 (dd, J = 2.4 and 12.4 Hz, 1H),7.54 (t, J = 8.4 Hz, 1H), 7.50-7.44 (m, 1H), 7.38-7.30 (m, 4H), 7.30-7.23 (m, 1H), 3.82 (s, 2H), 3.24 (s, 3H), 3.07 (s, 3H). 26c 24

1-(4-(6-(4-N- Methylpiperazylcarbam oyl)thieno[3,2- d]pyrimidin-4-yloxy)3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.43 (s, 1H), 11.80 (s, 1H), 8.77 (s, 1H), 7.93 (s, 1H), 7.93(dd, J = 2.0 and 12.0 Hz, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.48 (dd, J =2.0 and 8.4 Hz, 1H), 7.38-7.30 (m, 4H), 7.30-7.24 (m, 1H), 3.82 (s, 2H),3.74-3.62 (m, 4H), 2.48- 2.36 (m, 4H), 2.25 (bs, 3H). 26d 25

1-(4-(6- (Methylcarbamoyl)thie no[3,2-d]pyrimidin-4- yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.42 (s, 1H), 11.80 (s, 1H), 9.10 (q, J = 4.4 Hz, 1H), 8.76 (s,1H), 8.23 (s, 1H), 7.92 (dd, J = 2.0 and 12.0 Hz, 1H), 7.54 (t, J = 8.8Hz, 1H), 7.48 (dd, 2.0 and 8.8 Hz, 1H), 7.36-7.30 (m, 4H), 7.30- 7.24(m, 1H), 3.82 (s, 2H), 2.87 (d, J = 4.4 Hz, 1H). 26e 26

1-(4-(6-(N-Methoxy-N- methylcarbamoyl)thieno [3,2-d]pyrimidin-4-yloxy)-3- fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.79 (s, 1H), 8.23 (s, 1H), 7.93 (dd, J = 2.0 and 11.6Hz, 1H), 7.55 (t, J = 8.8 Hz, 1H), 7.48 (dd, J = 2.0 and 8.8 Hz, 1H),7.36-7.30 (m, 4H), 7.30-7.24 (m, 1H), 3.87 (s, 3H), 3.82 (s, 2H), 3.39(s, 3H). 26f 27

1-(4-(6- Carbamoylthieno[3,2- d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.43 (s, 1H), 11.80 (s, 1H), 8.76 (s, 1H), 8.55 (bs, 1H), 8.29(s, 1H), 8.07 (bs, 1H), 7.93 (dd, J = 2.0 and 12 Hz, 1H), 7.54 (t, J =8.8 Hz, 1H), 7.48 (dd, J = 2.0 and 8.8 Hz, 1H), 7.36-7.30 (m, 4H),7.30-7.23 (m, 1H), 3.82 (s, 2H).

Example 281-(4-(5-Methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(31a) Step 1: 4-Chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (28)

To a stirred solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (27) (J.Org. Chem., 2001, 66, 17, 5723-5730) (643 mg, 4.15 mmol) in DMF (41 mL)was added NaH (60% in mineral oil, 330 mg, 8.3 mmol) in one portion at0C and the mixture was stirred for 1 h followed by addition of methyliodide (0.28 mL, 4.5 mmol). The reaction mixture was allowed to warm upto the room temperature, stirred for an additional hour and quenchedwith AcOH (1 mL) to form a suspension which was stirred for 10 min andconcentrated under reduced pressure to give a solid. This material wasdissolved in AcOEt, the solution was washed with cold saturated NaHCO₃solution and water, dried over Na₂SO₄, and concentrated to produce thetitle compound 28 as a pale yellow solid (640 mg, 93% yield). ¹H NMR(400 MHz, CD₃OD) δ(ppm): 8.51 (s, 1H), 7.75 (d, J=3.3 Hz, 1H), 6.62 (d,J=3.3 Hz, 2H), 4.15 (s, 1H). LRMS (M+1) 168.1 (100%), 170.1 (34%).

Step 2: 4-(2-Fluoro-4-nitrophenoxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine(29)

A suspension of 4-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (28) (300mg, 1.79 mmol), 4-nitro-2-fluorophenol (422 mg, 2.69 mmol) and cesiumcarbonate (1.2 g, 3.58 mmol) in diphenyl ether (18 mL) was stirredovernight at 140° C. The reaction mixture was cooled to roomtemperature, concentrated under reduced pressure and the residue wastriturated with Et₂O, filtered, and dried to afford the title compound29 as a grey solid (258 mg, 49% yield). LRMS (M+1) 289.1 (100%).

Step 3:4-(5-Methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorobenzenamine (30)

To a solution of 4-(2-fluoro-4-nitrophenoxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (29) (253.6 mg, 0.879 mmol) in AcOH (3 mL) at 90° C. wasadded iron powder (245 mg, 4.4 mmol). The mixture was stirred vigorouslyfor 10 min and filtered. The filtrate was concentrated under reducedpressure to produce a solid, which was dissolved in DCM. The resultantsolution was washed with cold NaHCO₃ solution and water, dried overNa₂SO₄ and concentrated to provide a residue which was purified bycolumn chromatography (eluent MeOH—CH₂Cl₂ 1:20) to afford the titlecompound 30 as a brown solid (120.6 mg, 53% yield). LRMS (M+1) 240.1(100%).

Step 4:1-(4-(5-Methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(31a)

To a solution of4-(5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorobenzenamine (30)(120.8 mg, 0.5 mmol) and benzyl isothiocyanate (0.1 mL, 0.55 mmol) inTHF (5 mL) was stirred 2 h at room temperature, concentrated underreduced pressure and the residue was subjected to a columnchromatography on silica gel, (eluent EtOAc-hexane 1:1) to afford thetitle compound 31a as a white solid (97.6 mg, 45%). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.42 (s, 1H), 11.79 (s,1H), 8.28 (d, J=0.6 Hz, 1H),7.88 (dd, J=2.3 Hz, J=12.1 Hz, 1H), 7.81 (d, J=3.1 Hz, 1H), 7.50 (t,J=8.4 Hz, 1H), 7.44 (dd, J=2.1 Hz, J=8.8 Hz, 1H), 7.33 (m, 4H), 7.28 (m,1H), 6.65 (dd, J=0.6 Hz, J=2.9 Hz, 1H), 4.10 (s, 3H), 3.83 (s, 2H). LRMS(M+1) 436.1 (100%).

Example 291-(4-(5-Ethyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(31b)

Title compound 31b was obtained according to the scheme 5 usingprocedures similar to the ones described for example 28 but using ethyliodide (instead of methyl iodide) in the step 1. Characterization of 31bis provided in table 4.

Example 301-(4-(5-Benzyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(31c)

Title compound 31c was obtained according to the scheme 5 usingprocedures similar to the ones described for the example 28 but usingbenzyl bromide (instead of methyl iodide) in the step 1.Characterization of 31c is provided in table 4.

TABLE 4

31b-c: Examples 29-30 Characterization of 31b-c (examples 29-30) Cpd ExR Name Characterization 31b 29 Et 1-(4-(5-Ethyl-5H-1H), ¹H NMR (400 MHz,DMSO-d₆) pyrrolo[3,2- δ (ppm): 12.4 (br, 1H), 11.8 (br, d]pyrimidin-4-8.3 (s, 1H), 7.90-7.85 (m, yloxy)-3- 2H), 7.54-7.41 (m, 2H), 7.40 (m,fluorophenyl)-3-(2- 4H), 7.29 (m, 1H), 6.63 (d, J = 3.1phenylacetyl)thiourea Hz, 1H), 4.46 (q, J = 7.0 Hz, J =14.3 Hz, 2H),3.83 (s, 2H), 1.46 (t, J = 7.0 Hz, 3H). LRMS (M + 1) 450.2 (100%). 31c30 —CH₂Ph 1-(4-(5-Benzyl-5H- ¹H NMR (400 MHz, DMSO-d₆) pyrrolo[3,2- δ(ppm): 12.34 (s, 1H), 11.79 (s, d]pyrimidin-4- 1H), 8.3 (s, 1H), 8.04(d, J = 3.1 yloxy)-3- Hz, 1H), 7.8 (dd, J = 2.3 Hz, J = 7.8fluorophenyl)-3-(2- Hz, 1H), 7.4 (m, 1H), 7.35-7.76phenylacetyl)thiourea (m, 11H), 6.7 (d, 3.1 Hz, 1H), 5.66 (s, 2H), 3.82(s, 2H). LRMS (M + 1) 512.3 (100%).

Example 311-(4-(7-Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(36a)

Title compound 36a (scheme 6) was obtained according to the proceduressimilar to the ones described for the example 28 (scheme 5) but using asa starting material 4-chloro-7H-pyrrolo[2,3-d]pyrimidine 32 (instead ofchloride 27). Characterization of 36a is provided in table 5.

Example 321-(4-(7-Ethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(36b)

Title compound 36b was obtained according to the scheme 6 using theprocedures similar to the ones described for the example 31 but usingethyl iodide (instead of methyl iodide) in the step 1. Characterizationof 36b is provided in table 5.

Example 331-(4-(7-Benzyl-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(36c)

Title compound 36c was obtained according to the scheme 6 using theprocedures similar to the ones described for the example 31 but usingbenzyl bromide (instead of methyl iodide) in the step 1.Characterization of 36c is provided in table 5.

TABLE 5

36a-c: Examples 31-33 Characterization of 36a-c (examples 31-33) Cpd ExR Name Characterization 36a 31 Me 1-(4-(7-Methyl-7H- ¹NMR (400 MHz,DMSO-d₆) pyrrolo[2,3-d]pyrimidin-4- δ (ppm): 12.43 (s, 1H), 11.79 (s,1H), yloxy)-3-fluorophenyl)-3- 8.34 (s, 1H), 7.87 (dd, J = 1.8 Hz,(2-phenyl acetyl)thiourea J = 13.1 Hz, 1H), 7.55 (d, J = 3.5 Hz, 1H),7.44 (m, 2H), 7.33 (m, 4H), 7.27 (m, 1H), 6.62 (d, J = 3.5 Hz, 1H), 3.83(m, 5H). LRMS (M + 1) 436.1 (100%). 36b 32 Et 1-(4-(7-Ethyl-7H- ¹NMR(400 MHz, DMSO-d₆) pyrrolo[2,3-d]pyrimidin-4- δ (ppm): 12.41 (br, 1H),11.78 (br, yloxy)-3-fluorophenyl)-3- 1H), 8.32 (s, 1H), 7.87 (m, 1H),7.63 (2-phenyl acetyl)thiourea (d, J = 3.5, Hz, 1H), 7.43 (in, 2H), 7.33(m, 4H), 7.27 (m, 1H), 6.63 (d, J = 3.5 Hz, 1H), 4.29 (q, J = 7.2 Hz, J= 14.5 Hz, 2H), 3.82 (s, 2H), 1.40 (t, J = 7.2 Hz, 3H). LRMS (M +1)450.2 (100%). 36c 33 —CH₂Ph 1-(4-(7-Benzyl-7H- ¹H NMR (400 MHz, DMSO-d₆)pyrrolo[2,3-d]pyrimidin-4- δ (ppm): 12.41 (s, 1H), 11.79 (s, 1H),yloxy)-3-fluorophenyl)-3- 8.35 (s, 1H), 7.87 (m, 1H), 7.68 (d, (2-phenylacetyl)thiourea J = 3.5 Hz, 1H), 7.44 (m, 2H), 7.35- 7.23 (m, 10H), 6.68(d, 3.5 Hz, 1H), 5.48 (s, 2H), 3.82 (s, 2H). LRMS (M + 1) 512.3 (100%).

Example 347-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N-diisobutylthieno[3,2-b]pyridine-2-carboxamide(81) Step 1: Methyl 7-chlorothieno[3,2-b]pyridine-2-carboxylate (37)

To a stirred solution of 2 (7.0 g, 41.3 mmol) in anhydrous THF (100 mL)at −78° C. under a nitrogen atmosphere was added n-BuLi (24.7 mL, 2.5 Min hexanes, 61.8 mmol). After 1 hour, methyl chloroforrnate (9.6 ml, 124mmol) was added and the reaction mixture was stirred for an extra hourat the same temperature, quenched with excess methanol and allowed towarm to room temperature. The solvent was then evaporated and theresidue was purified by flash chromatography using hexane —AcOEt (70:30)as an eluent. The product from the column was re-crystallized from ethylacetate to afford title compound 37 (4.3g, 46% yield) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 8.75 (dd, J=0.8 and 4.8 Hz, 1H), 8.26(d, J=0.8 Hz, 1H), 7.74 (dd, J=0.8 and 5.2 Hz, 1H), 3.93 (s, 3H).

Step 2: Methyl7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboxylate (38)

A mixture of 37 (4.0 g, 17.6 mmol), 2-fluoro-4-nitrophenol (5.5 g, 35.0mmol) and K₂CO₃ (12.1 g, 87.5 mmol) in Ph₂O was heated at 180° C. for 5hours. The mixture was cooled to room temperature, diluted with EtOAcand washed with water. The organic phase was collected, dried overanhydrous sodium sulfate and the solvents were removed under reducedpressure. The residue was purified by flash chromatography usinghexane—AcOEt (70:30) as an eluent. The product from the column wasre-crystallized from a mixture of ethyl acetate-hexanes to afford 38(3.6 g, 59% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm):8.69 (d, J=5.2 Hz, 1H), 8.47 (dd, J=2.4 and 10.0 Hz, 1H), 8.27 (s, 1H),7.77 (dd, J=8.0 and 9.2 Hz, 1H), 7.06 (dd, J=0.8 and 5.2 Hz, 1H), 3.93(s, 3H).

Step 3: 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboxylicacid (39)

To a stirred solution of 38 (2.5 g, 7.18 mmol) in THF (50 ml) was addedKOH (14.3 ml, 1.0 N in H₂O, 14.3 mmol). After 4 hours the reactionmixture was concentrated and the resultant residue was dissolved in H₂O(50 ml). The aqueous layer was then washed with ethyl acetate andacidified with 1N HCl (pH=1). The precipitate that formed uponacidification was collected by filtration, washed with water and driedunder high vacuum to afford title compound 39 (2.3 g, 96% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ(pm): 8.68 (d, J=5.2 Hz, 1H),8.47 (dd, J=2.8 and 10.4 Hz, 1H), 8.20 (m, 1H), 8.17 (s, 1H), 7.76 (dd,J=8.0 and 8.8 Hz, 1H), 7.04 (d, J=5.2 Hz, 1H).

Step 4: 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carbonylchloride (40)

To a solution of 39 (2.0 g, 5.98 mmol) in anhydrous CH₂Cl₂ (30 ml) underan atmosphere of nitrogen, was added oxalyl chloride (2.6 ml, 29.8mmol). After stirring for 2 hours the solvent was evaporated, anhydroustoluene (10 mL) was added and the resultant mixture was evaporated(procedure of addition of toluene followed by evaporation was performedtwice) to afford title compound 40 (2.2 g, 94% yield) as a white solid.The product was used without further purification and characterizationand was assumed to be the mono-HCl salt.

Step 5:7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N-diisobutylthieno[3,2-b]pyridine-2-carboxamide(81)

To a solution of 40 (150 mg, 0.385 mmol) and TEA (107 μl, 0.771 mmol) inanhydrous CH₂Cl₂ under an atmosphere of nitrogen was addeddiisobutylamine (67 μL, 0.385 mmol). After stirring for 1 hour, methanol(2 mL) was added followed by iron powder (150 mg) and HCl (conc., 0.4mL). The reaction mixture was stirred for additional 2 hours and thenpartitioned between ethyl acetate (20 mL) and a mixture of H₂O (20 mL)and NH₄OH (2 mL). Organic phase was collected, washed with brine, driedover anhydrous MgSO₄, filtered and evaporated. The residue was treatedwith 2-phenylacetyl isothiocyanate (102 mg, 0.58 mmol) in THF (2 mL),the resultant mixture was allowed to stand for 2 hours at ambienttemperature, quenched with methanol (5.0 mL), loaded onto 5 ml of silicagel and purified by flash chromatography using hexane—AcOEt (70:30) asan eluent, to afford title compound 81 (41 mg, 18%) as a white solid. ¹HNMR (400 MHz, CD₃OD) δ (ppm): 8.54 (d, J=5.6 Hz, 1H), 8.08 (dd, J=2.0and 12.0 Hz, 1H), 7.69 (s, 1H), 7.38-7.49 (m, 2H), 7.28 - 7.35 (m, 5H),6.77 (dd, J=1.2 and 5.6 Hz, 1H), 3.77 (s, 2H), 3.46 (bs, 4H), 2.18 (bs,1H), 2.02 (bs, 1H), 1.02 (bs, 6H), 0.87 (bs, 6H). LRMS (M+1):592.7(calcd), 593.3 (found).

TABLE 6

8m-y: Examples 35-47 Characterization of compounds 8m-y (examples 35-47)Cmp Ex R Name Characterization 8m 35

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid furan-2- ylmethyl-methyl-amide¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s, 1H), 11.82 (s, 1H), 8.59(d, J = 5.6 Hz, 1H), 7.92-8.05 (m, 2H), 7.67 (bs, 1H), 7.54 (m, 2H),7.25-7.3 7 (m, 5H), 6.75 (d, J = 0.8, 5.2 Hz, 1H), 6.46 (s, 2H), 4.74(bs, 2H), 3.83 (s, 2H), 3.27 (bs, 1.5H), 2.99 (bs, 1.5 H). LRMS (M +1):574.6 (cald), 575.2 (found). 8n 36

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid (2- diisopropylamino-ethyl)-amide, formate salt 12.45 (s, 1H), 11.78 (s, 1H), 8.92 (t, J =5.6 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 8.16 (s, 1H), 8.12 (s, 1H), 7.99(m, 1H), 7.50 (m, 2H), 7.21-7.30 (m, 5H), 6.69 (d, J = 5.2 Hz, 1H), 3.79(s, 2H), 3.22 (m, 2H), 2.97 (m, 2H), 2.55 (t, J = 7.6 Hz, 2H), 0.964 (d,J = 6.4 Hz, 12H). LRMS (M + 1) .607.8 (calcd.), 608.3 (found). 8o 37

1-{3-Fluoro-4-[2- (pyrrolidine-1- carbonyl)-thieno[3,2-b]pyridin-7-yloxy]- phenyl}-3-phenylacetyl- thiourea ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.48 (s, 1H), 11.82 (s, 1H), 8.58 (d, J = 5.3 Hz,1H), 8.03 (m, 2H), 8.00 (s, 1H), 7.53 (m, 2H), 7.33 (m, 4H), 7.28 (m,1H), 6.73 (d, J = 5.3 Hz, 1H), 3 86 (t, J = 6.4 Hz, 2H), 3.83 (s, 2H),3.53 (t, J = 6.84 Hz, 2H), 1.95-1.86 (m, 4H). LRMS (M + 1). 534. 6(calcd.), 535.2 (found). 8p 38

(R)-N-(3-Fluoro-4-(2- (3-hydroxypyrrolidine- 1-carbonyl)thieno[3,2-bg]pyridin-7- yloxy)phenylcar- bamothioyl)- 2-phenylacetamide ¹H NMR(400 MHz, DMSO-d₆) δ (ppm): 12.48 (s, 1H), 11.81 (s, 1H), 8.59 (d, J=5.6Hz, 1H), 8.04 (m, 2H), 7.54 (m, 2H), 7.22-7.34 (m, 5H), 6.74 (d, J=5.2Hz, 1H), 5.07 (bs, 1H), 4.36 (bd, J=19.6 Hz, 1H), 3.99 (m, 1H), 3.82 (s,2H), 3.38-3.68 (m, 3H), 1.80-2.06 (m, 2H). MS (m/z): 551.1 (M + H)(found). 8q 39

(S)-N-(3-Fluoro-4-(2- (3-hydroxypyrrolidine- 1-carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR(DMSO-d₆) δ (ppm): 12.51 (s, 1H), 11.84 (s, 1H), 8.62 (d. 1H, J=5.3 Hz),8.08- 8.01 (m, 2H), 7.56-7.52 (m, 2H), 7.36-7.31 (m, 4H), 7.28-7.24 (m,1H), 6.77 (d, 1H, J=5.7 Hz), 4.38-4.32 (m, 1H), 4.00-3.92 (m, 1H), 3.81(s, 2H), 3.67-3.55 (m, 4H), 2.06-1.83 (m, 2H). MS (m/z): 551.1 (M + H)(found). 8r 40

(S)-1-(7-(2-Fluoro-4-(3-(2- phenylacetyl)thioureido) phenoxy)thieno[3,2-b]pyridine-2- carbonyl)pyrrolidine-2- carboxamide LRMS (M + 1) 577.6(calcd.), 578.3 (found). 8s 41

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid (2-cyano-ethyl)-cyclopropyl-amide LRMS (M + 1): 573.7 (calcd.), 574.2 (found). 8t42

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid (2- dimethylamino-ethyl)-amide, formate salt LRMS (M + 1): 551.7 (cald), 552.2 (found) 8u 43

7-[2-Fluoro-4-(3- phenylacetyl- thioreido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid bis-(2- methoxy-ethyl)-amideLRMS (M + 1): 596.7 (cald), 597.3 (found). 8v 44

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid benzylamide LRMS (M + 1): 570.7(calcd), 571.3 (found). 8w 45

7-[2-Fluoro-4-(3- phenylacetyl- thioureido)-phenoxy]-thieno[3,2-b]pyridine-2- carboxylic acid (2-cyano- ethyl)-phenyl-amideLRMS (M + 1): 609.7 (calcd.), 610.2 found. 8x 46

(R)-N-(1-amino-4- methyl-1-oxopentan-2- yl)-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido) phenoxy)thieno[3,2- b]pyridine-2-carboxamideLRMS (M + 1): 593.6 (calcd), 594.2 (found). 8y 47

7-[2-Fluoro-4-(3- phenylacetyl-thioureido)- phenoxy]-thieno[3,2-b]pyridine-2-carboxylic acid (2,5-dimethyl-2H- pyrazol-3-yl)-amide LRMS(M + 1): 574.6 (calcd), 575.2 (found)

Example 48N-(4-(2-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(44) Step 1. 2-Bromo-7-chlorothieno[3,2-b]pyridine (41)

To a stirred solution of the chloride 2 (10.12 g, 5.59 mmol) in dry THF(200 ml) at −78° C. was added n-BuLi (24 ml, 76.7 mmol, 2.5 M solutionin hexanes) and the resultant suspension was stirred for 15 minutes.Bromine (18.9 g, 120 mmol) was added slowly and the reaction mixture wasstirred for additional 30 min, quenched with water and diluted withEtOAc. The organic phase was collected, dried over anhydrous sodiumsulfate, filtered and concentrated under reduced pressure. Purificationby column chromatography (9:1 EtOAc/hexane) afforded title compound 41(10.5 g, 71% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm):8.62 (d, J=5.09 Hz, 1H), 7.92 (s, 1H), 7.59 (d, J=5.09 Hz, 1H).

Step 2. 2-Bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (42)

A mixture of the bromide 41 (5.1 g, 20.5 mmol), potassium carbonate(5.65 g, 4 mmol) and 2-fluoro-4-nitrophenol (4.82 g, 30.7 mmol) washeated at 190° C. in diphenyl ether (25 ml) for 3 hrs. After cooling toroom temperature it was diluted with DCM and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (eluent EtOAc:hexane, 3:1) to afford titlecompound 42 as a yellow solid (5.4 g, 71% yield). ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 8.55 (d, J=5.28 Hz, 1H), 8.46 (dd, J=2.5 and 10.4 Hz,1H), 8.19 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.72 (t, J=8.4 Hz), 6.99 (d,J=5.47 Hz, 1H).

Steps 3-4.1-(4-(2-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(44)

To a solution of the nitro compound 42 (100 mg, 0.27 mmol) in THF (2 ml)and water (0.5 ml) was added SnCl₂2H₂O (76.99 mg, 1.5 eq, 0.41 mmol) andthe reaction mixture was refluxed for 3 hrs, cooled to room temperature,diluted with EtOAc and washed with conc. ammonium hydroxide solution.EtOAc-extract was collected and the aqueous fractions were combined andwashed with DCM. DCM extract was combined with the AcOEt-extract, themixture was dried over sodium sulfate, filtered and evaporated to formthe amine 43 (92 mg, 100%), which was used without any furtherpurification.

To a solution of the amine 43 (92 mg, 0.27 mmol) in THF (10 ml) wasadded benzyl isothiocyanate (72 mg, 1.5 eq, 0.407 mmol). The reactionmixture was stirred for 1 hr at room temperature, concentrated underreduced pressure and the residue was purifed by column chromatograpy(7:3 hexane:EtOAc to 1:1 MeOH:EtOAc) to afford the title compound 44 asa white solid (28 mg, 20% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.48 (s, 1H), 11.81 (s, 1H), 8.55-8.52 (m, 1H), 8.01 (d, J=11.9 Hz,1H), 7.85 (s, 1H), 7.55-7.49 (m, 2H), 7.45-7.19 (m, 5H), 6.73 (d, J=5.7Hz, 1H), 3.82 (s, 2H). MS (m/z): 518.2/520.2 (M+H).

Example 49N-(3-Fluoro-4-(2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(47a) Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridine(45)

A mixture of the nitro compound 42 (500 mg, 1.36 mmol),6-methoxypyridin-3-ylboronic acid (312 mg, 2.04 mmol) and CsF (620 mg,4.08 mmol) were suspended in DME (12 ml) and NaHCO₃ (342 mg, 4.08 mmol),dissolved in the minimum amount of water, was added. The mixture wasde-aerated by bubbling N₂ through the solution for 10 min, heated at 80°C. for 3 hrs and concentrated to dryness. The formed residue wasdissolved in DCM and washed with water. The DCM was collected, driedover sodium sulfate, filtered and the DCM was removed by evaporation.The resultant solid was triturated with Et₂O to afford the titlecompound 45 (176 mg, 32% yield), which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.71 (m, 1H), 8.56 (m1H), 8.46 (m, 1H), 8.22 (m, 2H), 8.01 (s, 1H), 7.72 (t, J=8.6 Hz, 1H),6.99 (d, J=5.47 Hz, 1H), 6.90 (m, 1H), 3.97 (s, 3H).

Step 2.N-(3-Fluoro-4-(2-(6-methoxypyridin-3-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(47a)

To a solution of 45 (176 mg, 0.44 mmol) in MeOH (10 ml) and THF (10 ml)at 0° C. was added NiCl₂×6H₂O (210 mg, 0.89 mmol) and NaBH₄ (65 mg, 1.76mmol). The reaction mixture was stirred for 1 hr, concentrated todryness and the resultant solid was dissolved in 1 M HCl. The acidicsolution was then made basic with aqueous ammonium hydroxide andextracted with EtOAc. The organic phase was collected, dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the residue was triturated with Et₂O to afford theamine 46 as a white solid which was used immediately in the next step.

To a suspension of the amine 46 (162 mg, 0.44 mmol) in THF (7 ml) wasadded 2-phenylacetyl isothiocyanate (117 mg, 0.66 mmol). The reactionmixture was stirred for 1 hr, concentrated under reduced pressure andthe residue was purified by column chromatography (eluent EtOAc-MeOH,95:5); a solid was obtained which was triturated with Et₂O to affordtitle compound 47a (80 mg, 33% yield). ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.50 (s, 1H), 11.85 (s, 1H), 8.70 (s, 1H), 8.68 (d, J=6.07 Hz,1H), 8.28 (m, 1H), 8.10 (s, 2H), 7.59 (s, 2H), 7.34-7.27 (m, 5H), 7.01(d, J=8.61 Hz, 1H), 6.93 (d, J=5.7 Hz, 1H), 3.93 (s, 3H), 3.83 (s, 2H).

Examples 50-54

Examples 50-54 (compounds 47b-f) were prepared similarly to the compound47a (example 49) according to the scheme 9.

TABLE 7

47b-f: Examples 50-54 Characterization of compounds 47b-f (examples50-54) Cpd Ex R Name Characterization 47b 50

N-(3-Fluoro-4-(2- (6-fluoropyridin-3- yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2- phenylacetamide ¹H NMR (400 MHz,DMSO-d₆) δ ppm): 12.46 (s, 1H), 11.82 (s, 1H), 8.79 (m, 1H), 8.55 (d,J=5.48 Hz, 1H), 8.50 (m, 1H), 8.19 (s, 1H), 8.02 (d, J=13 Hz, 1H), 7.53(m, 1H), 7.37-7.26 (m, 6H), 6.68 (m, 1H), 6.68 (m, 1H), 3.82 (s, 2H).47c 51

N-(3-Fluoro-4-(2- (pyrimidin-5-yl)- thieno[3,2-b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2-phenylacetamide dihydochloride. H NMR(400 MHz, DMSO-d6) δ ppm): 12.48 (s, 1H), 11.83 (s, 1H), 9.2 (bs, 3H)8.63 (m, 1H), 8.34 (s, 1H), 8.03 (d, J=11 Hz, 1H), 7.55 (m, 2H), 7.30(m, 6H), 6.68 (m, 1H), 3.82 (s, 2H). 47d 52

N-(3-Fluoro-4-(2- (1-methyl-1H-pyrrol- 2-yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamo- thioyl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d6)δ (ppm): 8.46 (d, J=5.9 Hz, 1H), 8.04 (m, 1H), 7.59 (s, 1H), 7.51 (m,2H), 7.3-7.2 (m, 6H), 7.01 (s, 1H) 6.58 (d, J=5.9 Hz, 1H), 6.53 (m, 1H),6.10 (m, 1H), 3.87 (s, 3H), 3.81 (s, 2H). 47e 53

N-(3-Fluoro-4-(2- (furan-3-yl)thieno[3,2- b]pyridin-7-yloxy)-phenylcarbamothioyl)- 2-phenylacetamide 1H NMR (DMSO) δ (ppm): 12.49 (s,1H), 11.84 (s, 1H), 8.49 (d, J=5.5 Hz, 1H), 8.36 (s, 1H), 8.00 (d, J=11.3 Hz, 1H), 7.85-7.83 (m, 1H), 7.82 (s, 1H), 7.52-7.51 (m, 2H), 7.34-7.33 (m, 4H), 7.28-7.26 (m, 1H), 7.09 (brs, 1H), 6.62 (d, J=5.3 Hz, 1H),3.82 (s, 2H), MS (m/z) 504.0 (M + H) 47f 54

1-(3-Fluoro-4-(2- (4-methylthiophen- 3-yl)thieno[3,2-b]pyridin-7-yloxy)- phenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (DMSO) δ(ppm): 12.49 (s, 1H), 11.84 (s, 1H), 8.52 (d, J=5.5 Hz, 1H), 8.01 (d,J=5.6 Hz, 1H), 7.94 (d, J=2.7 Hz, 1H), 7.70 (s, 1H), 7.54-7.52 (m, 2H),7.41-7.40 (m, 1H), 7.35-7.34 (m, 3H), 7.33 (s, 1H), 7.27 (m, 1H), 6.64(dd, J=4.7 Hz, 1H), 3.82 (s, 2H), 2.43 (s, 3H), MS (m/z) 534.0 (M + H).

Example 55N-(3-Fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide (50) Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridine(48)

To a solution of 42 (461 mg, 1.3 mmol, scheme 8) in DME (4 mL) was added4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane(500 mg, 2.5 mmol), CsF (391 mg, 3.8 mmol), Pd(PPh₃)₄ (72 mg, 63 μmol)and NaHCO₃ (315 mg, 3.8 mmol) pre-dissolved in H₂O (1 ml). The reactionmixture was purged with nitrogen and refluxed for 2 hours. The DME wasremoved under reduced pressure and the aqueous layer was extracted withEtOAc. The extract was dried over sodium sulphate, filtered andevaporated to form a residue which was purified by column chromatography(eluent EtOAc/hexane, 1:1) to afford the title compound 48 (97 mg, 18%yield) as a white solid. ¹HNMR (DMSO) δ (ppm): 8.63 (d, J=1.2 Hz, 1H),8.49 (d-d, J=2.7 Hz, 1H), 8.33 (s, 1H), 8.22-8.19 (m, 2H), 8.16 (s, 2H),8.02 (d, J=8.6 Hz, 2H), 7.75 (t, J=8.0 Hz, 1H), 7.77-7.58 (m, 2H),7.58-7.50 (m, 2H), 6.97 (d, J=5.5 Hz, 1H), 3.33 (s, 3H), MS (m/z): 444.8(M+H).

Step 2.3-Fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(49)

Nitro compound 48 (97 mg, 2 mmol) was dissolved in a mixture of THF (7mL) and MeOH (15 mL); NiCl₂.×6H₂O (130 mg, 0.5 mmol) was added and thesolution was cooled to 0° C. To the cooled mixture NaBH₄ (42 mg, 1.1mmol) was added portion wise. The reaction was stirred for 20 min andquenched with 2 M HCl. The solvents were removed under reduced pressureand the residue was treated with concentrated ammonium hydroxidesolution (pH 10) and extracted with EtOAc. The organic extract was driedover anhydrous sodium sulfate, filtered and evaporated. The residue waspurified by column chromatography (eluent EtOAc) to afford the titlecompound 49 (46.7 mg, 51% yield) as a white solid. ¹H NMR (DMSO) δ(ppm): 8.52 (d, J=5.5 Hz, 1H), 8.25 (s, 1H), 8.15 (d, J=8.4 Hz, 2H),8.03 (d, J=8.4 Hz, 2H), 7.63-7.58 (m, 2H), 7.56-7.52 (m, 2H), 7.13 (t,J=8.6 Hz, 1H), 6.61 (d, J=2.2 Hz, 1H), 6.56 (dd, J=10 Hz, 1H), 6.46 (dd,J=5.7 Hz, 1H), 5.57 (s, 2H), 3.29 (s, 3H), MS (m/z): 414.8 (M+H).

Step 3.N-(3-Fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(50)

To a solution of 49 (46.7 mg, 0.1 mmol) in dry THF (5 mL),2-phenylacetyl isothiocyanate (40 mg, 0.2 mmol) was added and thereaction was allowed to stir for 30 minutes. The THF was removed underreduced pressure and the resultant product was purified by columnchromatography on silica gel, eluent hexane/EtOAc (1:1), to afford thetitle compound 50 (35.4 mg, 53% yield). ¹HNMR (DMSO) δ (ppm): 12.49 (s,1H),1 1.85 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d,J=8.4Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.52 (m, 5H), 7.34 (d, J=4.1Hz, 2H), 6.71 (d, J=5.3 Hz, 1H), 3.82 (brs, 2H), 3.27 9s, 3H) MS (m/z)592.0 (M⁺).

Example 561-(3-Fluoro-4-(2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(55) Step 1.(4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methanol(51)

To a solution of 42 (1.0 g, 2.71 mmol) in dry DME (20 ml) was added4-(hydroxymethyl)phenylboronic acid (823 mg, 5.4 mmol), NaHCO₃ (682 mg,8.13 mmol), CsF (820 mg, 5.4 mmol) and water (10 mL) and the reactionmixture was refluxed under nitrogen for 2 hrs. After cooling to roomtemperature the DME was removed under reduced pressure, the residue wasdissolved in EtOAc and the organic solution was washed with water, driedover anhydrous sodium sulfate, filtered and evaporated. The resultantsolid residue was triturated with Et₂O to afford the title compound 51as a white solid (880 mg, 82% yield). MS (m/z): 397.1 (M+H).

Step 2.2-(4-(Chloromethyl)phenyl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(52)

The alcohol 51 (880 mg, 2.22 mmol) was suspended in SOCl₂ (10 ml) andthe reaction mixture was refluxed for 1 hour, cooled and carefullypoured onto ice/water. A precipitate was formed which was collected byfiltration, washed with additional cold water and dried under vacuum toafford the title compound 52 (919 mg, 100% yield), which was usedwithout additional purification. MS (m/z): 415.1(100%) (M+H), 417.1(36%) (M+H).

Step 3.7-(2-Fluoro-4-nitrophenoxy)-2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridine(53)

To a suspension of 52 (823 mg, 1.82 mmol) in DMF (10 ml) was addedmorpholine (317 mg, 3.65 mmol) and the reaction mixture was heated for 4hours at 60° C., the solvent was removed under reduced pressure and theresidual solid was triturated with EtOAc and collected by filtration. Itwas further washed with EtOAc until no color was observed in thefiltrate, to form the title compound 53 (800 mg, 94% yield), which wasused without additional purification. ¹HNMR (DMSO) δ (ppm): 8.57 (d,J=4.7 Hz, 1H), 8.46 (dd, J=2.7 and 10.4 Hz, 1H), 8.18 (m, 1H), 8.07 (s,1H), 7.83 (d, J=12.2 Hz, 1H), 7.71 (t, J=8.02 Hz, 1H), 7.42 (d, J=8.2Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 3.56 (m, 4H), 3.51 (m, 2H), 3.33 (m,2H), 2.50 (m, 2H).

Step 4.1-(3-Fluoro-4-(2-(4-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(55)

To a solution of 53 (1.1 g, 2.37 mmol) in MeOH (20 mL) and THF (20 mL)at 0° C. was added NiCl₂×6H₂O (1.12 g, 4.73 mmol) and NaBH₄ (350 mg,9.48 mmol). The reaction mixture was allowed to stir for 1 hr, solventswere removed under reduced pressure and the resultant solid residue wasdissolved in 1 M HCl. This solution was made basic with concentratedaqueous ammonium hydroxide and extracted with EtOAc. The organic phasewas collected, dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure and the resultant solidwas triturated with Et₂O to afford the amine 54 as a white solid (1.02g, 100% yield), which was used in the next step without furtherpurification.

To a suspension of the amine 54 (1.02 g, 2.34 mmol) in THF (10 mL) wasadded 2-phenylacetyl isothiocyanate (622 mg, 3.52 mmol) and the reactionmixture was stirred for 1 hr at room temperature, concentrated underreduced pressure and purified by column chromatograpy (eluentEtOAc:MeOH, 95:5) to afford title compound 55 as a yellow powder (288mg, 12% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.48 (s, 1H), 11.84(s, 1H), 8.63 (m, 1H), 8.18 (s, 1H), 8.01 (d, J=7.8 Hz, 2H), 7.75 (m,2H), 7.57 (s, 2H), 7.33 (m, 4H), 6.80 (d, J=11.7 Hz, 2H), 3.83 (s, 5H),3.37 (d, J=11.7 Hz, 2H), 3.12 (m, 2H). MS (m/z) 613.3 (M+H).

Example 571-(3-Fluoro-4-(2-(3-morpholinoprop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(58) Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(3-morpholinoprop-1-ynyl)thieno[3,2-b]pyridine(56)

To a solution of bromide 42 (100 mg, 0.27 mmol) in THF (5 ml) was added4-(prop-2-ynyl)morpholine (68 mg, 0.54 mmol) [H-W. Tsou, et. al. J. Med.Chem., 2001, 44, 2719-2734], triethylamine (68 mg, 0.67 mmol), CuI (5mg, 0.03 mmol) and Pd(PPh₃)₂Cl₂ (5.3 mg, 7.56 μmol). The reactionmixture was degassed with nitrogen and refluxed for 2 hrs, cooled toroom temperature and adsorbed onto silica. Purification by columnchromatography (eluent EtOAc) afforded the title compound 56 as a beigesolid (88 mg, 79%). MS (m/z): 397.1 (M+H).

Steps 2-3.1-(3-Fluoro-4-(2-(3-morpholinoprop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(58)

To a solution of the nitro compound 56 (300 mg, 0.724 mmol) in THF (10mL) and NH₄Cl (6 mL) was added SnCl₂×2H₂O (489 mg, 2.17 mmol) and thereaction mixture was refluxed for 3 hrs. After cooling the mixture wasdiluted with EtOAc and washed with concentrated aqueous ammoniumhydroxide. EtOAc phase was separated and the aqueous phase was extractedwith DCM. Both EtOAc phase and DCM extract were combined, dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated todryness to afford the amine 57 (277 mg, 100% yield), which was usedwithout further purification.

To a solution of the amine 57 (270 mg, 0.74 mmol) in THF (10 mL) wasadded 2-phenylacetyl isothiocyanate (188 mg, 1.06 mmol) and the reactionmixture was stirred for 1 hr, concentrated under reduced pressure andpurified by column chromatography (eluent EtOAc) to afford titlecompound 58 (37 mg, 10% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.47 (s, 1H), 11.82 (s, 1H), 8.55 (d, J=5.3 Hz, 1H),8.01 (d, J=13.2 Hz, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.33 (m, 4H), 7.28(m, 1H), 6.72 (d, J=5.3 Hz, 1H), 3.82 (s, 2H), 3.64 (s, 2H), 3.61 (m,5H), 2.51 (m, 4H). MS (m/z): 561.3 (M+H).

Example 582-((4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methylamino)ethanol (63) Step 1.2-{4-[7-(2-Fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridin-2-yl]-benzylamino}-ethanol(59)

To a suspension of the chloride 52 (500 mg, 1.1 mmol) in DME (10 mL) wasadded ethanolamine (336 mg, 5.5 mmol). The reaction mixture refluxed for2 hrs, the solvent was removed under reduced pressure; the residue wasdissolved in EtOAc and washed with water. The organic phase wascollected, dried over sodium sulfate, filtered and evaporated. Theremaining solid was triturated with Et₂O to afford the title compound 59as a yellow solid (200 mg, 41% yield). ¹H NMR (DMSO) δ (ppm): 8.57 (d,J=5.5 Hz, 1H), 8.47 (dd, J=2.7 and 10.4 Hz, 1H), 8.21 (m, 1H), 8.17 (s,1H), 7.83 (d, J=8.0 Hz, 1H), 7.71 (t, J=8.6 Hz, 1H), 7.44 (d, J=8.0 Hz,1H), 6.91 (d, J=5.5 Hz, 1H), 4.48 (t, J=5.5 Hz, 1H), 3.75 (s, 2H), 3.45(q, J=5.6 Hz, 2H), 3.33 (m, 1H), 3.15 (d, J=5.1 Hz, 2H), 2.56 (t, J=5.7Hz, 2H).

Step 2. Carbonic acid2-(tert-butoxycarbonyl-{4-[7-(2-fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridin-2-yl]-benzyl}-amino)-ethylester tert-butyl ester (60)

To a solution of 59 (200 mg, 0.45 mmol) in DCM (7 mL) at roomtemperature was added triethylamine (188 mg, 1.82 mmol), DMAP (cat) andBoc₂O (355 mg, 1.82 mmol). The reaction mixture was stirred at roomtemperature overnight, the DCM was removed under reduced pressure andthe residue was dissolved in EtOAc, washed sequentially with dilute HClsolution, saturated NaHCO₃ and brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was evaporated and the residue waspurified by column chromatography (eluent EtOAc:hexane, 3:7) to affordtitle compound 60 (200 mg, 69% yield) as a yellow oil. ¹H NMR (DMSO) δ(ppm): 8.58 (d, J=5.3 Hz, 1H), 8.47 (dd, J=2.7 and 10.3 Hz, 1H), 8.21(m, 1H), 8.09 (s, 1H), 7.87 (m, 2H), 7.72 (t, J=8.4 Hz, 1H), 7.33 (d,J=8.2 Hz, 2H), 6.91 (d, J=5.3 Hz, 1H), 4.44 (s, 2H), 4.07 (t, J=5.5 Hz,2H), 3.40 (m, 2H), 1.36 (m, 18H).

Steps 3-4. Carbonic acid2-[tert-butoxycarbonyl-(4-{7-[2-fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridin-2-yl}-benzyl)-amino]-ethylester tert-butyl ester (62)

To a solution of 60 (500 mg, 1.1 mmol) in MeOH (10 mL) at 0° C. wasadded NiCl₂×6H₂O (148 mg, 0.63 mmol) and NaBH₄ (46 mg, 1.24 mmol). Thereaction mixture was allowed to stir for 1 hr, concentrated to drynessand the resultant solid was dissolved in 1 M HCl. The acidic solutionwas then made basic with concentrated ammonium hydroxide solution andextracted with EtOAc. The organic phase was collected, dried overanhydrous sodium sulfate and filtered. The filtrate was evaporated underreduced pressure and the resultant solid was triturated with Et₂O toafford the crude amine 61 as a white solid (190 mg, 100% yield), whichwas used for the next step without characterization and additionalpurification.

To a suspension of the amine 61 (190 g, 0.31 mmol) in THF (7 mL) wasadded 2-phenylacetyl isothiocyanate (118 mg, 0.62 mmol) and the reactionmixture was stirred for 1 hr at room temperature, concentrated underreduced pressure and purified by column chromatography (eluentEtOAc-MeOH, 6:4) to afford title compound 62 as a yellow powder (190 mg,77% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.48 (s, 1H), 11.83 (s,1H), 8.51 (s, 1H), 8.04 (s, 1H), 8.01 (d, J=11.7 Hz, 1H), 7.86 (d, J=7.7Hz, 2H), 7.52 (m, 2H), 7.34 (m, 6H), 7.32 (m, 1H), 6.64 (d, J=5.5 Hz,1H), 4.43 (s, 2H), 4.07 (t, J=5.3 Hz, 2H), 3.81 (s, 2H), 3.44 (m, 2H),1.37 (m, 18H).

Step 5.1-(3-Fluoro-4-(2-(4-((2-hydroxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(63)

To a solution of 62 in DCM (190 mg, 0.24 mmol) was added TFA (excess) atroom temperature and the reaction mixture was stirred for 3 hrs,evaporated under reduced pressure and the residual solid was trituratedwith Et₂O to afford the title compound 63 as the di-TFA salt (100 mg,51% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.49 (s, 1H), 11.84 (s,1H), 8.89 (s, 1H), 8.53 (d, J=5.1 Hz, 1H), 8.14 (s, 1H), 8.01 (m, 1H),7.62 (dd, J=2.5 and 7.7 Hz, 2H), 7.54 (d, J=2.7 Hz, 2H), 7.33 (m, 4H),7.28 (m, 1H), 6.67 (d, J=5.5 Hz, 1H), 4.64 (m, 1H), 4.30 (m, 1H), 4.22(t, J=5.3 Hz, 2H), 3.82 (s, 2H), 3.63 (t, J=5.3 Hz, 2H), 2.98 (m, 1H).MS (m/z) 587.0 (M+H).

To a solution of 2-methoxyethanamine (900 mg, 12 mmol) in DME (15 mL)was added 3-bromobenzylbromide (2.5 g, 10 mmol) and the reaction mixutrewas stirred at 40° C. (scheme 14). After 30 minutes, Et₃N (1.01 g, 10mmol) was added and the reaction was allowed to stir for another 10minutes, filtered and the filtrate was concentrated to afford bromide 64as a colorless oil (2.0 g, 80% yield). MS (m/z): 244.1/246.1 (M+H).tert-Butyl 3-bromobenzyl(2-methoxyethyl)carbamate (65)

To a solution of compound 64 (997 mg, 4 mmol) in CH₂Cl₂ (12 mL),di-tert-butylcarbonate (1.8 g, 8 mmol) was added and the reactionmixture was stirred for 3 hrs (scheme 14). DMAP (cat.) was added to thesolution and the reaction mixture was allowed to stir for additional 76hours. Solvent was removed under reduced pressure and the crude productwas purified by column chromatography, eluent EtOAc/hexane (1:10) toafford the title compound 65 (778 mg, 56% yield) as a colorless oil. MS(m/z): 368.1/370.1 (M+Na).

TABLE 8 Aryl bromides 66-70 prepared according to the scheme 14 Aminereagent used Characterization to obtain the Cpd Aryl bromide Chemicalname MS (m/z) aryl bromides 66

tert-Butyl 3- bromobenzyl(2- morpholinoethyl)carbamate 399.1/401.1 (M +H)

67

tert-Butyl 4- bromobenzyl(2- methoxyethyl)carbamate 344.1/346.1 (M + H)

68

tert-Butyl 2- bromobenzyl(2- methoxyethyl)carbamate 365.9/367.9 (M + Na)

69

1-(4-Bromobenzyl)-1H- tetrazole 238.9/240.9 (M + H)

70

tert-Butyl 4- bromobenzyl((tetrahydro furan-2-yl)methyl)carbamate370.1/372.1 (M + H)

bis-tert-Butyl 2-(3-bromobenzylamino)ethyl(methyl)carbamate (71)

To a solution of tert-butyl2-tert-butyloxycarbonylaminoethyl(methyl)carbamate (600 mg, 2.2 mmol) indry THF (5 mL) at 0° C., was added NaH (91 mg, 3.8 mmol) and thereaction was stired for 30 minutes. 3-Bromobenzylbromide was added andthe reaction was refluxed for 3 hours, cooled to room temperature andpoured into MeOH. Solvents were removed under reduced pressure and theproduct was partitioned between EtOAc and water. Organic phase wascollected and dried over anhydrous sodium sulphate, filtered andevaporated. The crude product was purified by column chromatography onsilica gel, eluent EtOAc/hexane (1:5), to afford the title compound 71(672 mg, 80% yield) as a colourless oil. MS (m/z): 343.0/345.0 (M-Boc).

Example 59N-(3-Fluoro-4-(2-(3-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(76a) Step 1. tert-Butyl2-methoxyethyl(3-(pinacolatoborolan-2-yl)benzyl)carbamate (72)

To a solution of bromide 65 (778 mg, 2.3 mmol), in dry toluene (12 mL),was added the bis(pinacolato)diboron (872 mg, 3.4 mmol), KOAc (677 mg,6.9 mmol) and Pd(PPh₃)₄ (80 mg, 69 μmol). The reaction mixture waspurged with nitrogen, refluxed for 2 hours and was allowed to cool toroom temperature. The solvent was removed under reduced pressure and theresidue was partitioned between DCM and water (30 mL/30 mL). The organicphase was collected and dried over anhydrous sodium sulphate, filteredand evaporated. The remained solid was purified by columnchromatography, eluent EtOAc/hexane (1:10) to afford title compound 72(577 mg, 64% yield) as a colorless oil. ¹H NMR (DMSO) δ (ppm): 7.54-7.52(m, 2H), 7.33-7.31 (m, 2H), 4.39 (s, 2H), 3.40-3.35 (m, 2H), 3.33-3.25(m, 2H), 3.20 (s, 3H), 1.43-1.32 (m, 9H), 1.28 (s, 12H).

Step 2. tert-Butyl3-(7-(2-fluoro-4-nitrophenoxy)thieno{3,2-b}pyridine-2-yl)benzyl(2-methoxyethyl)carbamate(73)

To a solution of the bromo-nitro compound 42 (272 mg, 0.7 mmol) in DME(4 mL), was added pinacolate 72 (578 mg, 1.5 mmol), CsF (226 mg, 2.2mmol), Pd(PPh₃)₄ (43 mg, 37 μmol) and NaHCO₃ (186 mg, 2.2 mmol)pre-dissolved in water (2 mL). The reaction mixture was purged withnitrogen, refluxed for 1 hour, cooled to room temperature and thesolvent was removed under reduced pressure. The residue was extractedwith EtOAc, the extract was dried over anhydrous sodium sulfate,filtered and concentrated to produce a brown oil which was purified bychromatography on silica gel, eluent EtOAc, to afford the title compound73 (347 mg, 85% yield) as a white solid. ¹H NMR (DMSO) δ (ppm): 8.60 (d,J=5.3 Hz, 1H), 8.47 (d-d, J=7.6 Hz, 1H), 8.19 (d, J=6.5 Hz, 1H), 8.07(s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.73-7.69 (m, 2H), 7.48 (t, J=7.8 Hz,1H), 7.30 (d, J=7.4 Hz, 1H), 6.95 (d, J=5.5 Hz, 1H), 4.48 (s, 2H), 3.21(s,3H), 2.50 (q, J=2.2 Hz, 4H), 1.44-1.33 (m, 9H), MS (m/z): 554.0(M+H).

Step 3. tert-Butyl3-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)benzyl(2-methoxyethyl)carbamate(74)

To a solution of 73 (347 mg, 0.6 mmol) in THF (4 mL) and MeOH (2 mL),NiCl₂ (372 mg, 1.6 mmol) was added and the solution was cooled to 0° C.NaBH₄ (95 mg, 2.5 mmol) was added portion wise. After 20 minutes, thereaction was treated with 2 M HCl and solvents were removed underreduced pressure. The concentrated mixture was basified to pH 10 withammonium hydroxide solution and the mixture was extracted with EtOAc,the extract was dried over anhydrous sodium sulfate, filtered andevaporated. The residue was purified by silica gel columnchromatography, eluent EtOAc, to afford the title compound 74 (235 mg,72% yield) as a white solid. ¹H NMR (DMSO) δ (ppm): 8.47 (d, J=5.6 Hz,1H), 7.97 (s, 1H), 7.77 (d, J=7.2 Hz, 1H), 7.70 (s, 1H), 7.48 (t, J=7.6Hz, 1H), 6.56-6.51 (m, 2H), 6.44 (dd, J=6.3 Hz, 1H), 5.54 (s, 2H), 4.84(s, 2H), 3.43 (s, 2H), 3.23 (s, 3H), 2.50 (q, J=2.2 Hz, 4h), 1.46-1.35(m, 9H).

Step 4. tert-Butyl3-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl(2-methoxyethyl)carbamate(75)

To a solution of 74 (235 mg, 0.5 mmol) in dry THF (5 mL), 2-phenylacetylisothiocyanate (159 mg, 0.9 mmol) was added and the reaction was allowedto stir for 30 min. The solvent was removed under reduced pressure andthe resulting product was purified by chromatography on silica gel usingEtOAc/hexane (1:1) as eluting system to give the desired product (440mg, 90%) as a white solid. ¹H NMR (DMSO) δ (ppm): 8.52 (d, J=5.3 Hz,1H), 8.01 ( t, J=6.5 Hz, 2H), 7.79 (d, J=7.4 Hz, 1H), 7.70 (s, 1H),7.53-7.52 (m, 2H), 7.47 (t, J=7.6 Hz, 1H), 7.34 (d, J=4.5 Hz, 4H),7.30-7.24 (m, 2H), 6.67 (d, J=5.3 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H),3.42 (s, 2H), 3.22 (s, 3H), 2.50 (q, J=2.2 Hz, 4H), 1.45-1.33 (m, 9H).

Step 5.N-(3-Fluoro-4-(2-(3-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(76a)

To a solution of 75 (440 mg, 0.6 mmol) in DCM (10 mL), TFA (145 μL, 1.9mmol) was added and the reaction was stirred for 12 hours, concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography, eluent MeOH/EtOAc (1:10), to afford the titlecompound 76a (227 mg, 63% yield) as a light yellow solid. ¹H NMR (DMSO)δ (ppm): 8.54 (d, J=5.5 Hz, 1H), 8.07 (s, 1H), 8.02-8.0 (m, 2H), 7.93(d-t, J=2.0 Hz, 1H), 7.55-7.53 (m, 4H), 7.34-7.32 (m, 4H), 7.29-7.26 (m,1H), 6.68 (d, J=5.3 Hz, 1H), 4.19 (s, 2H), 3.81 (s, 1H), 3.57 (t, J=4.9Hz, 2H), 3.33 (s, 2H), 3.29 (s, 3H), 3.08 (t, J=4.9 hz, 2H), 2.84 (q,J=2.2 Hz, 4H).

Examples 60-65

Compounds 76b-g (examples 60-65) were synthesized similarly to thecompound 76a (example 59) according to the schemes 14-15, starting frombromides 66-69 and 71. Characterization of 76b-g is provided in Table8a.

TABLE 8a

76b-g: Examples 60-65 Characterization of compounds 76b-g (examples60-65) Cpd Ex Z Chemical name Characterization 76b 60

1-(3-Fluoro-4-(2- (2-((2-methoxyethylamino)- methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)- 3-(2-phenylacetyl)thiourea ¹H NMR (400MHz,DMSO-d₆) δ ppm): 12.50 (s, 1H), 11.83 (s, 1H), 8.57 (d, J=5.5 Hz, 1H),8.03-8.00 (m, 1H), 7.76-7.74 (m, 2H), 7.61- 7.50 (m, 5H), 7.36-7.25 (m,5H), 6.70 (d, J=5.3 Hz, 1H), 4.32 (s, 2H), 3.81 (s, 2H), 3.52 (t, J=5.1Hz, 2H), 3.16 (s, 3H), 3.08 (t, J= 4.7 Hz, 2H), MS (m/z): 601.0 (M + H).76c 61

1-(3-Fluoro-4-(2-(3-((2- morpholinoethylamino)-methyl)phenyl)thieno[3,2- b]pyridin-7- yloxy)phenyl)-3-(2-phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d6) δ (ppm): 12.49 (s, 1H),11.85 (s, 1H), 8.56 (d, J=5.1 Hz, 1H), 8.09-7.98 (m, 5H), 7.61-7.55 (m,5H), 7.33 (s, 1H), 7.27 (brs, 2H), 6.70 (d, J=5.1 Hz, 1H), 4.30 (brs,2H), 3.82 (brs, 2H), 3.73 (brs, 4H), MS (m/z) 656.2 (M + H). 76d 62

N-(3-Fluoro-4-(2- (4-((2-(methylamino)ethyl amino)methyl)phenyl)-thieno[3,2-b]pyridin-7- yloxy)phenyl- carbamothioyl)- 2-phenylacetamide1H NMR (DMSO): 12.49 (s, 1H), 11.84 (s, 1H), 8.51 (d, J=5.5 Hz),8.04-7.99 (m, 2H), 7.87 (d, J=7.6 Hz, 2H), 7.54-7.53 (m, 2H), 7.34- 7.33(m, 5H), 7.29-7.22 (m, 2H), 6.64 (d, J=5.5 Hz, 1H), 4.42-4.39 (m, 2H),3.82 (s, 2H), 3.29 (brs, 2H), 3.23 (brs, 3H), 2.78-2.76 (m, 2H), MS:calcd 599.74, found 800.1 (M + H). 76e 63

1-(3-Fluoro-4-(2-(4-((2- methoxyethylamino)- methyl)phenyl)thieno-[3,2-b]pyridin-7- yloxy)phenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400MHz, DMSO-d₆) δ ppm): 12.48 (s, 1H), 11.83 (s, 1H), 9.02 (s, 2H), 8.54(d, J=5.5 Hz, 1H), 8.13 (s, 1H), 8.02 (d, J=13.3 Hz, 1H), 7.97 (d, J=8.2Hz, 2H), 7.53 (m, 2H), 7.33 (m, 4H), 7.28 (m, 2H), 6.67 (d, J=5.5 Hz,1H), 4.22 (m, 2H), 3.83 (s, 2H), 3.59 (t, J=4.9 Hz, 2H), 3.31 (s, 3H),3.12 (m, 2H), MS (m/z): 601.2 (M + H). 76f 64

1-(3-Fluoro-4-(2-(3-((2- (methylamino)ethyl amino)methyl)phenyl)-thieno[3,2-b]pyridin- 7-yloxy)phenyl)-3-(2- phenylacetyl)thiourea ¹H NMR(DMSO) δ (ppm): 12.49 (s, 1H), 11.85 (s, 1H), 8.55 (d, J= 5.09 Hz, 1H),8.08 (s, 1H), 8.04 (brs, 1H), 8.00-7.97 (m, 2H), 7.62- 7.53 (m, 4H),7.36-7.32 (m, 4H), 7.29-7.26 (m, 1H), 6.69 (d, J=5.5 Hz, 1H), 4.31 (brs,2H), 3.82 (s, 2H), 3.31-3.27 (m, 4H), 2.63 (s, 3H), MS (m/z) 600.2 (M +H). 76g 65

1-(4-(2-(4-((1H-Tetrazol- 1-yl)methyl)phenyl)- thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)- 3-(2-phenylacetyl)thiourea ¹H NMR (DMSO) δ(ppm): 12.46 (s, 1H), 11.82 (s, 1H), 9.54 (s, 1H), 8.51 (dd, J=1.1 and5.09 Hz, 1H), 8.1 (s, 1H), 7.96 (d, J=23.3 Hz, 1H), 7.90 (d, J=6.7 Hz,2H), 7.53 (m, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.32 (m, 4H), 7.26 (m, 1H),6.65 (d, J=5.5 Hz, 1H), 5.78 (s, 2H), 3.82 (s, 2H). MS (m/z) 596.1 (M +H).

Example 661-(3-Fluoro-4-(2-(4-(((tetrahydrofuran-2-yl)methylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(81) Step 1.tert-Butyl(4-(7-chlorothieno[3,2-b]pyridin-2-yl)phenyl)methyl((tetrahydrofuran-2-yl)methyl)carbamate (77)

To a solution of the trimethyltin compound 9 (1.4 g, 3.06 mmol) (scheme2) and bromide 70 (2.25 g, 6.11 mmol) (scheme 14, Table 8) in drytoluene (50 ml) was added Pd(PPh₃)₄ (176 mg, 0.153 mmol). The reactionmixture was refluxed overnight, cooled to room temperature and thesolvents were removed under reduced pressure. The resultant solid wastriturated with hexane/ether and then purified by column chromatography,eluents EtOAc/Hexane 1:9, then EtOAc:hexane 4:6, to afford titlecompound 77 as a white solid (1.2 g, 86% yield). MS (m/z): 459.2/461.2(M+H).

Step 2. tert-Butyl(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methyl((tetrahydrofuran-2-yl)methyl)carbamate(78)

To a solution of 77 (1.0 g, 2.18 mmol) in Ph₂O (10 ml) was added2-fluoro-4-nitrophenol (856 mg, 5.45 mmol) and potassium carbonate (904mg, 6.55 mmol). The reaction mixture was heated at 180° C. for 4 hrs,cooled to room temperature, diluted with DCM, filtered and concentrated.The residue was purified by column chromatography, eluent EtOAc:hexane8:2, to afford title compound 78 (250 mg, 20% yield). MS (m/z): 580.3(M+H).

Steps 3-4. tert-Butyl(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methyl((tetrahydrofuran-2-yl)methyl)carbamate(80)

To a solution of 78 (250 mg, 0.431 mmol) in MeOH (10 mL) at 0° C. wasadded NiCl₂×6H₂O (205 mg, 0.86 mmol) and NaBH₄ (64 mg, 1.72 mmol). Thereaction mixture was allowed to stir for 1 hr, concentrated to drynessand the resultant solid was dissolved in 2 M HCl. This solution was thenmade basic with concentrated aqueous ammonium hydroxide and extractedwith DCM. The DCM extract was dried over anhydrous sodium sulfate,filtered and evaporated to form the amine 79 (236 mg, 100% yield), whichwas used without characterization and further purification.

To a solution of the amine 79 (236 mg, 0.43 mmol) in THF (10 mL) wasadded 2-phenylacetyl isothiocyanate (114 mg, 6.44 mmol). The reactionmixture was stirred for 1 hr, concentrated and the residue was purifiedby column chromatograpy, eluent—gradient from EtOAc:hexane 1:1 to EtOAc,to afford title compound 80 (200 mg, 64% yield) as a white solid. MS(m/z): 725.5 (M+H).

Step5.1-(3-Fluoro-4-(2-(4-(((tetrahydrofuran-2-yl)methylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea(81)

To a solution of 80 (200 mg, 0.28 mmol) in toluene (5 mL), TFA (excess)was added. The reaction mixture was allowed to stir overnight, thesolvent was removed under reduced pressure and the remained solid wastriturated with diethyl ether to afford title compound 81 as the di-TFAsalt (130 mg, 57% yield). ¹H NMR (DMSO) δ (ppm): 12.47 (s, 1H), 11.83(s, 1H), 9.06 (s, 2H), 8.53 (dd, J=2.0 and 5.5 Hz, 1H), 8.13 (s, 1H),8.0 (d, J=12.1 Hz, 1H), 7.97 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H),7.53 (m, 2H), 7.32 (m, 4H), 7.27 (m, 1H), 6.68 (d, J=5.8 Hz, 1H), 4.23(m, 1H), 3.82 (s, 2H), 3.78 (m, 1H), 3.71 (m, 1H), 3.11 (m, 1H), 2.95(m, 1H), 2.0 (m, 1H), 1.98 (m, 2H), 1.56 (m, 1H). MS (m/z) 627.3 (M+H).

Example 677-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid methoxy-methyl-amide (85) Step 1.7-Chloro-N-methoxy-N-methylthieno[3,2-b]pyridine-2-sulfonamide (82)

To a solution of chloride 2 (scheme 1) (700 mg, 4.14 mmol) in THF (20ml) was added n-BuLi (2 ml, 4.97 mmol, 2.5 M solution in hexanes) at−78° C. and the reaction mixture was stirred for 20 mins. SO₂-gas waspassed over the surface of the solution for 3 hrs at the sametemperature, then for an additional hr at 0° C. The reaction mixture wasevaporated. DCM (20 ml) and NCS (605 mg, 4.55 mmol) were added and thereaction mixture was stirred at room temperature for 1.5 hrs, filteredthrough a celite pad and concentrated to produce a pink solid. The solidwas dissolved in acetone (20 ml); MeNH(OMe) hydrochloride (608 mg, 6.21mmol) and triethylamine (627 mg, 6.21 mmol) were added and the reactionmixture was stirred at room temperature overnight. The solvent wasremoved under reduced pressure and the residue was dissolved in EtOAc.The EtOAc solution was washed with water, dried over anhydrous sodiumsulfate, filtered and evaporated. The residue was purified by columnchromatography (eluent EtOAc:hexane, 1:1) to afford the title compound82 (485 mg, 40% yield) as a pink solid. MS (m/z) 561.1 (M+H).

Step 2.7-(2-Fluoro-4-nitrophenoxy)-N-methoxy-N-methylthieno[3,2-b]pyridine-2-sulfonamide(83)

A mixture of 82 (400 mg, 1.37 mmol), 2-fluoro-4-nitrophenol (321 mg,2.05 mmol) and K₂CO₃ (756 mg, 5.48 mmol) were heated to 190° C. indiphenyl ether (55 ml) for 3 hrs. The mixture was cooled to roomtemperature, diluted with DCM and filtered. The filtrate wasconcentrated and purified by column chromatography (eluent EtOAc:hexane,1:1) to afford title compound 83 (225 mg, 40% yield). MS (m/z) 414.0(M+H).

Steps 3-4.7-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid methoxy-methyl-amide (85)

To a solution of the nitro compound 83 (225 mg, 0.54 mmol) in THF (5 ml)and water (2 ml) was added SnCl₂×2H₂O (742 mg, 3.3 mmol). The reactionmixture was refluxed for 3 hrs, diluted with EtOAc and washed withaqueous ammonium hydroxide. The washings were combined and extractedwith DCM. Both EtOAc- and DCM- phases were combined, dried overanhydrous sodium sulfate, filtered and evaporated to produce the amine84 (168 mg, 81% yield), which was used without characterization andfurther purification.

To a solution of the amine 84 (225 mg, 0.59 mmol) in THF (8 ml) wasadded phenyl-acetyl isothiocyanate (208 mg, 1.18 mmol). The reactionmixture was stirred for 1 hr, concentrated under reduced pressure andpurified by column chromatography (eluent EtOAc) to afford 85 (323 mg,98% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.52(s, 1H), 11.86 (s, 1H), 8.74 (d, J=5.3 Hz, 1H), 8.33 (s, 1H), 8.07 (d,J=13.5 Hz, 1H), 7.61 (m, 2H), 7.36 (m, 4H), 7.29 (m, 1H), 3.86 (s, 3H),3.84 (s, 2H), 2.96 (s, 3H), MS (m/z): 561.3 (M+H).

Example 687-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonicacid amide (86)

Title compound 86 was obtained following the procedures described forthe compound 85 (example 67, scheme 16) but substituting in the firststep O-methyl hydroxylamine for ammonia. ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 13.82 (s, 1H), 13.15 (s, 1H), 9.98 (m, 1H), 9.4-9.2 (m, 4H), 8.87(s, 2H), 8.64 (m, 5H), 8.15 (s, 1H), 3.82 (s, 2H). MS (m/z): 517.3(M+H).

Example 691-(4-(2-(1-Ethyl-5-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl-3-(2-(2-methoxyphenyl)acetyl)thiourea(90) Step 1.7-Chloro-2-(1-ethyl-5-methyl-1H-imidazol-4-yl)-thieno[3,2-b]pyridine(87)

To a solution of 2 (1.14 g, 6.76 mmol) in THF (60 ml) was added, at −78°C., n-BuLi (3.38 ml, 2.5 M soln in hexanes) and the reaction mixture wasstirred at the same temperature for 10 min. A solution of ZnCl₂ (16.9ml, 2.5 ml, 0.5M in THF) was added and the reaction mixture was warmedto room temperature. Then a solution of1-ethyl-4-iodo-5-methyl-1H-imidazole (800 mg, 3.38 mmol) (Pyne, S. G andCliff, M. D. Synthesis 1994, 681) and Pd(PPh₃)₄ (390 mg, 0.34 mmol) inTHF (15 ml) were added and the reaction mixture was refluxed for 3 hrs,cooled to room temperature, quenched with conc. ammonium hydroxidesolution and made neutral with concentrated aqueous HCl. The neutralsolution was extracted with EtOAc, the extract was collected, dried overanhydrous sodium sulfate, and filtered. The filtrate was evaporated andthe residue was purified by column chromatography (eluent MeOH:EtOAc,1:9) to afford the title compound 87 (1.1 g, 100% yield) as a brown oil.MS (m/z) 278.0/280.0 (M+H).

Step 2.2-(1-Ethyl-5-methyl-1H-imidazol-4-yl)-7-(2-fluoro-4-nitro-phenoxy)-thieno[3,2-b]pyridine(88)

A suspension of 87 (650 mg, 2.35 mmol), potassium carbonate (970 mg,7.04 mmol) and 2-fluoro-4-nitrophenol (738 mg, 4.7 mmol) were heated at190° C. in diphenyl ether (15 ml) for 3 hrs. The mixture was cooled toroom temperature, diluted with DCM and filtered. The filtrate wasconcentrated and the residue was purified by column chromatography(eluents EtOAc, then MeOH:EtOAc, 1:9) to afford title compound 88 (600mg, 64%) as a yellow solid. MS (m/z) 399.0 (M+H).

Steps3-4.1-(4-(2-(1-Ethyl-5-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-(2-methoxyphenyl)acetyl)thiourea(90)

To a solution of 88 (200 mg, 0.5 mmol) in MeOH (8 ml) and THF (2 ml) at0° C. was added NiCl₂×6H₂O (237 mg, 1 mmol) and NaBH₄ (74 mg, 2 mmol).The reaction mixture was allowed to stir for 1 hr, concentrated todryness and the resultant solid was dissolved in 1 M HCl. The acidicsolution was then made basic with concentrated aqueous ammoniumhydroxide and extracted with EtOAc. The organic phase was collected,dried over anhydrous sodium sulfate and filtered. The solvent wasevaporated under reduced pressure and the residue was triturated withEtOAc to afford the crude amine 89 (184 mg, 100% yield) which was usedimmediately in the next step [without characterization].

To a solution of the amine 89 (180 mg, 0.49 mmol) in THF (10 ml) wasadded (2-methoxy-phenyl)-acetyl isothiocyanate (200 mg, 0.98 mmol). Thereaction mixture was stirred for 10 min, concentrated and the residuewas purified by column chromatography (eluents EtOAc, then toMeOH-EtOAc, 1:9), to afford title compound 90 (84 mg, 30% yield) asyellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 12.56 (s, 1H), 11.73 (s,1H), 8.43 (d, J=5.5 Hz, 1H), 8.04 (d, J=12.3 Hz, 1H), 7.71 (s, 1H), 7.51(m, 4H), 7.25 (m, 2H), 6.97 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.2 Hz, 1H),6.97 (d, J=8.2 Hz, 1H), 6.92 (t, J=7.2 Hz, 1H), 6.56 (d, J=5.5 Hz, 1H),4.0 (q, J=3.2 Hz, 2H), 3.80 (s, 2H), 3.77 (s, 3H), 2.47 (s, 3H), 1.31(t, J=3.2 Hz, 2H). MS (m/z) 576.1 (M+H).

Example 70N-(3-Fluoro-4-(2-(1-(2-methoxyethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(96) Step 1.7-Chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridine(91)

To a solution of 2 (9.4 g, 56.0 mmol) in THF (150 ml) at −78° C. wasadded n-BuLi (28 ml, 70.0 mmol, 2.5 M soln in hexanes) and the reactionmixture was stirred at −78° C. for 45 mins. A solution of ZnCl₂ (140 ml,70.0 mmol, 0.5M in THF) was added and the reaction mixture was warmed toroom temperature. To the warmed mixture a solution of4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole [Carl J. Loveyet al, Tetrahedron Lett., 2004, 45(28), 5529-5532] (9.0 g, 28.0 mmol)and Pd(PPh₃)₄ (2.5 g, 2.1 mmol) in THF added. The reaction mixture washeated to reflux for 3 hrs, cooled to room temperature, quenched withaqueous ammonium hydroxide and made neutral with aqueous HCl. Theneutral solution was extracted with EtOAc, the organic phase wascollected, dried over anhydrous sodium sulfate and filtered. Thefiltrate was evaporated under reduced pressure and the residue waspurified by column chromatography (eluent MeOH-EtOAc, 1:20) to affordthe title compound 91 (7.5 g, 73% yield) as a brown oil. MS (m/z)366.0/368.0 (M+H).

Step 2.7-(2-Fluoro-4-nitrophenoxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridine(92)

A suspension of 91 (4.2 g, 11.5 mmol), potassium carbonate (7.95 g, 57.5mmol) and 2-fluoro-4-nitrophenol (4.97 g, 31.6 mmol) was heated at 190°C. in diphenyl ether (15 ml) for 4.5 hrs, cooled to room temperature,diluted with DCM and filtered. The filtrate was concentrated underreduced pressure and purified by column chromatography (eluents hexaneand acetone/hexane, 45:55) to afford title compound 92 (3.4 mg, 61%yield) as a yellow solid MS (m/z) 487.0 (M+H).

Step 3.7-(2-Fluoro-4-nitrophenoxy)-2-(1H-imidazol-4-yl)thieno[3,2-b]pyridine(93)

To a suspension of 92 (3.3 g, 6.8 mmol) in EtOH (8 ml) was addedconcentrated HCl (7 ml) and distilled water (4 ml). The mixture washeated at 80-90° C. for 2.5 h, cooled to room temperature andconcentrated under reduced pressure. The remaining residue was subjectedto azeotropic distillation with EtOH followed by neutralization withsaturated aqueous NaHCO₃. The solid that precipitated was filtered andwashed with water, and the filtrate was extracted with EtOAc. The solidand EtOAc extract were combined, evaporated under reduced pressure andthe residue was collected and dried to afford the title compound 93 (2.4g, 100% yield) as a yellow solid. MS (m/z) 357.0 (M+H).

Step 4.7-(2-Fluoro-4-nitrophenoxy)-2-(1-(2-methoxyethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridine(94)

To a solution of 93 (300 mg, 0.84 mmol) in dry DMF (3 ml) at 0° C. wasadded NaH (40 mg, 60% dispersion in oil, 1.0 mmol). The mixture wasallowed to warm to room temperature over 0.5 h then re-cooled to 0° C.Bromoethylmethyl ether (123 mg, 0.88 mmol) was added and mixture wasallowed to warm to room temperature over 20 hours, concentrated andpartitioned between EtOAc and water. The EtOAc phase was dried overanhydrous Na₂SO₄, filtered, concentrated and purified by columnchromatography (eluents hexane and acetone/hexane 75:25) to afford thetitle compound 94 (126 mg, 36% yield) as a pale yellow solid. MS (m/z)415.1.0 (M+H).

Step 5.3-Fluoro-4-(2-(1-(2-methoxyethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(95)

Following the procedure described above for compound 89 (scheme 17) butreplacing the nitro compound 88 with the nitro compound 94, titlecompound 95 was obtained as a beige solid (23 mg, 100% yield). MS (m/z)385.2 (M+H).

Step 6.N-(3-Fluoro-4-(2-(1-(2-methoxyethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(96)

Following the procedure described above for the compound 90 (scheme 17)but replacing the amine 89 with the amine 95 and using2-(2-methoxyphenyl)acetyl isothiocyanate instead of 2-phenylacetylisothiocyanate, title compound 96 was obtained as a beige solid (6 mg,17% yield). ¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 12.57 (1H, s), 11.77 (1H,s), 8.53 (1H, d, J=5.48 Hz), 8.08 (1H, d, J=12.03 Hz), 8.02 (1H, s),7.91 (1H, s), 7.76 (1H, s), 7.59-7.52 (2H, m), 7.28-7.21 (2H, m), 6.98(1H, d, J=8.22 Hz), 6.91 (1H, d, J=7.44 Hz), 6.71 (1H, d, J=5.67 Hz),4.21 (2H, t, J=4.89 Hz), 3.80 (2H, s), 3.77 (3H, s), 3.65 (2H, t, J=4.89Hz), 3.26 (3H, s). MS (m/z) 592.1 (M+H).

Example 71(S)—N-(3-Fluoro-4-(2-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(104) Step 1. (S)-1-(4-Bromobenzyl)pyrrolidin-3-ol (97)

Title compound 97 was obtained, according to the scheme 14 by reacting(S)-pyrrolidin-3-ol with 3-bromobenzylbromide, as a white solid (1.3 g63% yield). LRMS 256.1/258.1 (M+1).

Step 2. 7-Chloro-2-(tributylstannyl)thieno[3,2-b]pyridine (98)

To a solution of the chloride 2 (18.72 g, 110 mmol) in THF (200 mL) at−78° C. n-BuLi (51 mL, 127 mmol) was added and the reaction mixture wasstirred for about 30 minutes. The tributylchlorostannane (25.4 mL, 93mmol) was added and the mixture was stirred at −78° C. for another 60minutes, quenched with water [at the same temperature] and allowed towarm up to room temperature. The warmed mixture was extracted withEtOAc, the extract was dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The residue was purified by flashchromatography, eluents EtOAc-hexane (15:85), then EtOAc-hexane (25:75)to afford title compound 98 (30.2 g, 77% yield) as a yellow oil. LRMS(M+1) 459.1 (100%).

Step 3.(S)-1-(4-(7-Chlorothieno[3,2-b]pyridin-2-yl)benzyl)pyrrolidin-3-ol (99)

To a solution of 98 (2.44 g, 5.30 mmol) and bromide 97 (1.3 g, 5.07mmol) in dry toluene (30 mL) was added Pd(PPh₃)₄ (290 mg, 0.25 mmol).The reaction mixture was heated to reflux for 1.5 h, cooled to roomtemperature and the solvent was removed under reduced pressure. Theresultant solid was purified by column chromatography, eluentsEtOAc-Hexane (1:1) then MeOH/EtOAc (20:80), to afford title compound 99(1.24 g, 71% yield) as a white solid. MS (m/z): 345.1/347.1 (M+H).

Step 4.(S)-2-(4-((3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)methyl)phenyl)-7-chlorothieno[3,2-b]pyridine(100)

To a suspension of 99 (0.5 g, 1.45 mmol) in dry THF (7 ml) at 0° C. wasadded TBDMSOTf (0.5 ml, 2.2 mmol) and the reaction mixture was stirredfor 20 min. Et₃N (0.61 ml, 4.4 mmol) was added and mixture was stirredat the same conditions for another hour, quenched by the addition ofwater (˜2 ml) and concentrated to dryness. The remained solid waspartitioned between EtOAc and water. Organic phase was collected, washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by column chromatography, eluents EtOAc/hexane (1:1) thenMeOH/EtOAc (5:95) to afford title compound 100 (637 mg, 96% yield) as awhite solid. MS (m/z): 459.2/461.2 (M+H).

Step 5.(S)-2-(4-((3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)methyl)phenyl)-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine(101)

To a solution of 100 (250.0 mg, 0.54 mmol) in Ph₂O (4 ml) was added2-fluoro-4-nitrophenol (171 mg, 1.1 mmol) and potassium carbonate (304mg, 2.2 mmol). The reaction mixture was heated to 195° C. for 3 hrs,cooled to room temperature, diluted with DCM, filtered and concentrated.The residue was purified by column chromatography, eluents EtOAc, thenMeOH/EtOAc (20-80), to afford title compound 101 (94 mg, 30% yield) as awhite solid. MS (m/z): 580.3 (M+H).

Step 6.(S)—N-(4-(2-(4-((3-(tert-Butyldimethylsilyloxy)pyrrolidin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(103)

To a solution of the nitro compound 101 (90 mg, 0.16 mmol) in MeOH (4ml) at 0° C. was added NiCl₂×6H₂O (74 mg, 0.31 mmol) and NaBH₄ (23 mg,0.62 mmol). The reaction mixture was allowed to stir for 1 hr,concentrated to dryness and the resultant solid was dissolved in 2 MHCl. The acidic solution was then made basic with aqueous ammoniumhydroxide solution and extracted with EtOAc. The organic extract wasdried over anhydrous sodium sulfate, filtered and evaporated to form theamine 102 (80 mg, 95% yiled), which was used without furtherpurification and characterization.

To a solution of the amine 102 (80 mg, 0.15 mmol) in THF (2 mL) wasadded 2-phenylacetyl isothiocyanate (64 mg, 0.36 mmol).The reactionmixture was stirred for 1 hr, concentrated and the residue was purifiedby column chromatography, eluents EtOAc:hexane (1:1), then EtOAc, toafford title compound 103 (34 mg, 30% yield) as a white solid. MS (m/z):727.5 (M+H).

Step 7.(S)—N-(3-fluoro-4-(2-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(104)

To a solution of 103 (34 mg, 0.047 mmol) in CH₃CN/MeOH (0.5 mL/2.0 mL),concentrated HCl (8 drops) was added and the reaction was allowed tostir 2 h. The solvents were removed under reduced pressure and theresultant solid was triturated with diethyl ether followed bypurification by Gilson HPLC preparative system, column Aquasil C18 (25%MeOH in water to 100% MeOH), to afford title compound 104 (2.5 mg, 9%yield), as a white solid. ¹H NMR (DMSO) δ (ppm): 11.82 (1H, s), 8.51(1H, d, J=5.28 Hz), 8.23 (1H, s), 8.02-7.98 (2H, m), 7.82 (2H, d, J=7.83Hz), 7.52 (2H, br), 7.41 (2H, d, J=7.83 Hz), 7.33-7.25 (5H, m), 6.64(1H, d, J=5.09 Hz), 4.20 (1H, br), 3.83 (2H, s), 3.38 (2H, s), 2.34-2.32(2H, m), 2.03-1.96 (2H, m), 1.56 (2H, br). MS (m/z) 613.3 (M+H).

Example 72(S)-1-(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)pyrrolidine-2-carboxylicacid (106)

Step 1. (S)-tert-Butyl1-(4-bromobenzyl)pyrrolidine-2-carboxylate (105)

Title compound 105 was obtained, according to the scheme 14 by reacting(S)-tert-butyl pyrrolidine-2-carboxylate with 3-bromobenzylbromide, as awhite solid (1.62 g, 94% yield). LRMS 340.1/342.1 (M+1).

(S)-1-(4-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)benzyl)pyrrolidine-2-carboxylicacid (106)

Title compound 106 was obtained following the procedures similar to theones described above for the synthesis of compound 104 (example 71,scheme 19), replacing bromide 97 with the bromide 105 in the secondstep, skipping the step 4 (TBS-protection) and using in the last stepTFA/DCM mixture for tert-butyl ester de-protection. ¹H NMR (400MHz,DMSO-d₆): δ12.47 (1H, s), 11.82 (1H, s), 8.53 (1H, br), 8.13 (1H,s), 8.01 (1H, d, J=12.91 Hz), 7.96 (2H, d, J=7.02 Hz), 7.60 (2H, d,J=7.63 Hz), 7.54 (2H, br), 7.34-7.27 (5H, m), 6.67 (1H, d, J=5.09 Hz),4.40 (1H, br), 4.23 (1H, br), 3.83 (2H, s), 3.38 (2H, s), 2.38 (1H, br),2.00 (2H, br), 1.85 (1H, br). MS (m/z) 641.3 (M+H).

Examples 73-82 (Compounds 13i-13r)

Following the procedures described above for the synthesis of compound13a (example 12, scheme 2) but substituting trimethyltin chloride in thestep 1 for tributyltin chloride and 2-bromothiazole in the step 2 forheteroaryl bromides shown in the Table 9, title compounds 13i-13r weresynthesized. Characterization of compounds 13i-13r (examples 73-82) isprovided in the Table 10.

TABLE 9 Heteroaryl bromides used in the synthesis of compounds 13i-13r(examples 73-82) Heteroaryl bromide Preparation

McCullum, P., et al., Aust. J. Chem. 52(3), 1999, 159-166

McCullum, P., et al., Aust. J. Chem. 52(3), 1999, 159-166

Borai, M. El et al. Pol. J. Chem. 55, 1981, 1659

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790. d)Reference where BrCN is being used for such a purpose

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.

a) Begtrup, M.; Larsen, P.; Acta Chem. Scand. 44, 10; 1990; 1050-1057.b) Begtrup, M.; Bull. Soc. Chim. Belg.; 97; 8-9; 1988; 573-598. c)Begtrup, M.; Larsen, P.; Chem. Pharm. Bull. 42, 9; 1994; 1784-1790.

A commercial product

A commercial product

TABLE 10

Characterization of compounds 13i-13r (examples 73-82) Cpd Ex R NameCharacterization 13i 73

N-(4-(2-(1-Ethyl-1H- imidazol-2- yl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl- carbamothioyl)-2- phenylacetamide ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.48(1H, s), 11.81(1H, s), 8.52(1H, d, J=5.09Hz),8.02(1H, d, J=12.13Hz), 7.82(1H, s), 7.53-7.46(3H, m), 7.34-7.28(5H, m),7.06(1H, s), 6.68(1H, d, J=5.48Hz), 4.37(2H, q, J=6.85Hz), 3.83(2H, s),1.43(3H, t, J=7.24Hz) MS(m/z) 532.3(M+H) 13j 74

N-(3-Fluoro-4-(2-(1- isopropyl-1H- imidazol-2- yl)thieno[3,2-b]pyridin-7- yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H nmr (400MHz, DMSO-d₆) δ ppm 12.48(1H, s), 11.82(1H, s), 8.53(1H, d, J=5.38Hz),8.02(1H, d, J=12.13Hz), 7.81(1H, s), 7.60(1H, s), 7.53(2H, d, J=5.28Hz),7.34-7.26(5H, m), 7.09(1H, s), 6.68(1H, d, J=5.28Hz), 4.98(1H, quintet,J=6.46Hz), 3.83(2H, s), 1.49(6H, d, J=6.46Hz) MS(m/z) 546.3(M+H) 13k 75

N-(3-Fluoro-4-(2- (4-methyl-4H- 1,2,4-triazol-3- yl)thieno[3,2-b]pyridin-7- yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H nmr (400MHz, DMSO-d₆) δ ppm 12.45(1H, s), 11.78(1H, s), 8.56(1H, d, J=5.28Hz),8.16(1H, s), 8.02(s, 1H), 7.98(1H, s), 7.52(2H, s), 7.30-7.21(5H, m),6.72(1H, d, J=5.09), 4.16(3H, s), 3.78(2H, s) . MS(m/z) 519.2(M+H) 13l76

N-(3-Fluoro-4-(2-(1- methyl-1H-imidazol- 4-yl)thieno[3,2- b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H nmr (400 MHz,DMSO-d₆) δ ppm 44(1H, d, J=5.67Hz), 8.01(1H, d, J=12.13Hz), 7.85(1H, s),7.71(1H, s), 7.68(1H, s), 7.51-7.50(2H, m), 7.33-7.27(5H, m), 6.57(1H,d, J=5.48Hz), 3.83(2H, s), 3.72(3H, s) . MS(m/z) 518.2(M+H) 13m 77

N-(4-(2-(1-Ethyl-1H- imidazol-4- yl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl- carbamothioyl)-2- phenylacetamide ¹H nmr (400 MHz,DMSO-d₆) δ ppm 12.50(1H, s), 11.84(1H, s), 8.56(1H, d, J=5.87Hz),8.14(1H, s), 8.11-8.04(2H, m), 7.78(1H, s), 7.57-7.56(2H, m),7.35-7.56(5H, m), 6.76(1H, d, J=5.48Hz), 4.10(2H, q, J=7.24Hz), 3.84(2H,s), 1.44(3H, t, J=7.24Hz). MS(m/z) 532.2(M+H) 13n 78

N-(3-Fluoro-4-(2-(1- (2-morpholinoethyl)- 1H-imidazol-2- yl)thieno[3,2-b]pyridin-7- yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H nmr (400MHz, DMSO-d₆) δ ppm 12.49(1H, s), 11.82(1H, s), 8.52(1H, d, J=5.09Hz),8.02(1H, d, J=11.93Hz), 7.90(1H, s), 7.54-7.48(3H, m), 7.33-7.24(5H, m),7.06(1H, s), 6.69(1H, d, J=4.90Hz), 4.44(2H, s), 3.83(2H, s),3.55-3.51(4H, m), 2.71(2H, s), 2.50(2H, s) . MS(m/z) 617.3(M+H) 13o 79

N-(3-Fluoro-4-(2-(1- (2-morpholinoethyl)- 1H-pyrazol-4- yl)thieno[3,2-b]pyridin-7- yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H NMR(DMSO) δ (ppm): 12.46(1H, s), 11.81(1H, s), 8.45(1H, d, J=5.48Hz),8.33(1H, s), 8.01-7.99(2H, m), 7.69(1H, s), 7.51-7.49(2H, m),7.34-7.24(5H, m), 6.59(1H, d, J=5.48Hz), 4.26(2H, t, J=6.46Hz), 3.82(2H,s), 3.54(4H, t, J=4.40Hz), 2.74(2H, t, J=6.46Hz), 2.42(4H, br). MS(m/z)617.3 (M+H). 13p 80

N-(4-(2-(1-Ethyl-1H- pyrazol-4- yl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl- carbamothioyl)-2- phenylacetamide ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 12.49(s, 1H), 11.84(s, 1H), 8.47(d, J=5.6Hz, 1H),8.36(s, 1H), 8.02-7.99(m, 2H), 7.70(s, 1H), 7.58-7.51(m, 2H),7.39-7.32(m, 4H), 7.31-7.25(m, 1H), 6.60(d, J=5.6Hz, 1H), 4.18(q,J=7.2Hz, 2H), 3.83(s, 2H), 1.41(t, J=7.2Hz, 3H). 13q 81

N-(3-Fluoro-4-(2-(1- methyl-1H-pyrazol- 4-yl)thieno[3,2- b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 12.50(s, 1H), 11.85(s, 1H), 8.47(d, J=5.6Hz, 1H),8.31(s, 1H), 8.02(d, J=12.0Hz, 1H), 7.99(s, 1H), 7.70(s, 1H),7.55-7.52(m, 2H), 7.38-7.32(m, 4H), 7.31-7.28(m, 1H), 6.60(d, J=5.6Hz,1H), 3.89(s, 3H), 3.83(s, 2H). 13r 82

N-(3-Fluoro-4-(2-(6- morpholinopyrimidin- 4-yl)thieno[3,2- b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 12.48(s, 1H), 11.82(s, 1H), 8.60(s, 1H), 8.56(d,J=5.6Hz, 1H), 8.55(s, 1H), 8.03(d, J=12.0Hz, 1H), 7.66(s, 1H),7.58-7.52(m, 2H), 7.37-7.31(m, 4H), 7.31-7.24(m, 1H), 6.70(d, J=5.6Hz,1H), 3.82(s, 2H), 3.78-3.68(m, 8H).

Example 83N-(4-(2-(1H-Imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(113) Step 1. 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazole (107)

To a stirred suspension of NaH (60% dispersion in oil, 0.65 g, 16.2mmol) at 0° C. was added imidazole (1 g, 14.7 mmol) in THF (14 mL). Themixture was warmed to room temperature over 30 min, then re-cooled to 0°C. followed by an addition of (2-(chloromethoxy)ethyl)trimethylsilane(2.73 ml, 15.4 mmol). The combined mixture was warmed to roomtemperature over 1 h, quenched with saturated aqueous ammonium chloride,concentrated to dryness and partitioned between water and EtOAc. Organicphase was collected, dried over anhydrous sodium sulfate, filtered andevaporated. The residue was purified by column chromatography (eluentsEtOAc, then MeOH/EtOAc 20:80), to afford the title compound (2.04 g, 70%yield) as a white solid. MS (m/z) 199.3 (M+H).

Step 2. 2-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (108)

To a solution of 107 (100 mg, 0.50 mmol) in acetonitrile (1 mL) at roomtemperature was added cyanogen bromide (107 mg, 1.0 mmol) and themixture was allowed to stir at room temperature for 3 h, concentrated todryness and partitioned between EtOAc and water. The organic phase wascollected, dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified by column chromatography (eluentsEtOAc/hexane 25:75, then EtOAc), to afford the title compound 108 (45mg, 32% yield) as a colorless oil. MS (m/z) 277.0/279.0 (M+H).

Step 3.7-Chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thieno[3,2-b]pyridine(109)

Starting from the compound 98 (scheme 19) and following the proceduredescribed above for the synthesis of compound 10 (example 12, scheme 2)but substituting 2-bromothiazole in the step 2 for the bromide 108,title compound 109 was obtained as a white solid (22 mg, 41% yield). MS(m/z) 366.1/368.1 (M+H).

Step 4.7-(2-Fluoro-4-nitrophenoxy)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thieno[3,2-b]pyridine(110)

Following the procedure described above for the synthesis of compound 11(example 12, step 3, scheme 2) but substituting compound 10 for compound109, title compound 110 was obtained as a yellow solid (104 mg, 50%yield). MS (m/z) 487.3 (M+H).

Steps 5-6.N-(3-Fluoro-4-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(112)

Following the procedure described above for the synthesis of compound13a (example 12, steps 4-5, scheme 2) but substituting compound 11 forcompound 110 and using intermediate amine 111 (instead of amine 12),title compound 112 was obtained as a beige solid (48 mg, 33% yield). MS(m/z) 634.3 (M+H).

Step 7.N-(4-(2-(1H-Imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(113)

A solution of 112 (21 mg, 0.033 mmol) in 4N HCl in dioxane (3.5 mL) wasallowed to stir at 55° C. for 1 h. The mixture was then cooled andsolvent was removed under reduced pressure. The resultant gum wastriturated with ether several times to form a solid material that wasdried under high vacuum to afford the product 113 as a beige solid (5mg, 28% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.50 (1H, s), 11.84 (1H,s), 8.66 (1H, d, J=5.67 Hz), 8.39 (1H, s), 8.06 (1H, d, J=12.72 Hz),7.68 (2H, s), 7.59-7.58 (2H, m), 7.36-7.30 (5H, m), 6.86 (1H, d, J=5.48Hz), 3.83 (2H, s). MS (m/z) 504.1 (M+H).

Example 842-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-N-(2-morpholinoethyl)-1H-imidazole-5-carboxamide(117) Step 1. 1-Methyl-N-(2-morpholinoethyl)-1H-imidazole-5-carboxamide(115)

To a suspension of 1-methyl-1H-imidazole-5-carboxylic acid (0.92 g, 7.3mmol) [Rapoport, H., et al.; Synthesis 1988; 767.1] in dichloromethane(10 ml), was added oxalyl chloride (2.6 ml, 29.2 mmol) and the reactionmixture was heated to reflux for 1 h, cooled, concentrated to dryness toform acid chloride 114 (1.05 g, 100%) which was used withoutcharacterization and further purification.

To a suspension of the acid chloride 114 (1.05 g, 7.3 mmol) in THF (10mL) was added 2-morpholinoethanamine (2.38 g, 18.5 mmol). The mixturewas stirred at room temperature for 1 h, concentrated to dryness and theresidue was purified by column chromatography (eluentchloroform/MeOH/ammonium hydroxide, 100:2:0.5), to afford the titlecompound 115 (551 mg, 32% yield) as a white solid. MS (m/z) 239.1 (M+H).

Step 2.2-Bromo-1-methyl-N-(2-morpholinoethyl)-1H-imidazole-5-carboxamide (116)

To a solution of 115 (550 mg, 2.31 mmol) in acetonitrile (5 mL) wasadded cyanogen bromide (489 mg, 4.6 mmol). The reaction flask wascovered with aluminum foil and the mixture was allowed to stir at roomtemperature for 18 h. The solvent was removed under reduced pressure andthe residue was purified by column chromatography (eluents 100% EtOAc to30% MeOH/EtOAc), to afford title compound 116 as a beige solid (230 mg(31%). MS (m/z) 317.1/319.1 (M+H).

Step 3.2-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-N-(2-morpholinoethyl)-1H-imidazole-5-carboxamide(117)

Following the procedures described above for the synthesis of compound13a (example 12, scheme 2) but substituting trimethyltin chloride in thestep 1 for tributyltin chloride and 2-bromothiazole in the step 2 forthe bromide 116, title compound 117 was synthesized. ¹H NMR (400MHz,DMSO-d₆) δ ppm 8.55 (1H, d, J=5.28 Hz), 8.47 (1H, br), 8.04 (1H, s),7.97 (1H, d, J=12.52 Hz), 7.67 (1H, s), 7.49 (2H, br), 7.33-7.32 (4H,m), 7.26 (1H, m), 6.70 (1H, d, J=5.09 Hz), 4.18 (3H, s), 3.84 (2H, s),3.57 (4H, br), 2.47-2.33 (8H, m). MS (m/z) 674.3 (M+H).

Examples 85 and 86 Methyl2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1-H-imidazole-5-carboxylate(123), andN-(3-Fluoro-4-(2-(5-(hydroxymethyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(124) Step 1. Methyl 2-bromo-1-methyl-1H-imidazole-5-carboxylate (118)

Following the procedure described above for the compound 116 (scheme 21)but replacing compound 115 with methyl1-methyl-1H-imidazole-5-carboxylate, title compound 118 was obtained asa beige solid (373 mg, 49% yield). MS (m/z) 219.1/221.1 (M+H).

Step 2. Methyl2-(7-chlorothieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(119)

Starting from the compound 98 (scheme 19) and following the proceduredescribed above for the synthesis of compound 10 (example 12, scheme 2)but substituting 2-bromothiazole in the step 2 for the bromide 118,title compound 119 was obtained as a white solid (580 mg, 100% yield).MS (m/z) 308.1/310.0 (M+H).

Step 3. Methyl2-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(120)

Following the procedure described above for the synthesis of compound 11(example 12, step 3, scheme 2) but substituting compound 10 for compound119, title compound 120 was obtained as a yellow solid (254 mg, 31%yield). MS (m/z) 429.1 (M+H).

Step 4. Methyl2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(121) and(2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazol-5-yl)methanol(122)

Following the procedure described above for the synthesis of compound 12(example 12, step 4, scheme 2) but substituting compound 11 for compound120, title compounds 121 and 122 were obtained as white solids (39 mg,21% yield and 56 mg, 32% yield). MS (m/z) 399.1 (M+H) and MS (m/z) 371.1(M+H) respectively.

Step 5. Methyl2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1-methyl-1H-imidazole-5-carboxylate(123)

Following the procedure described above for the synthesis of compound13a (example 12, step 3, scheme 2) but substituting compound 12 forcompound 121, title compound 123 was obtained as a beige solid (35 mg,63% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.48 (1H, s), 11.82 (1H, s),8.58 (1H, dd, 5.48, 0.98 Hz), 8.13 (1H, d, J=0.98 Hz), 8.03 (1H, d,J=12.52 Hz), 7.81 (1H, d, J=1.17 Hz), 7.55-7.54 (2H, m), 7.36-7.31 (4H,m) 7.27 (1H, m), 6.74 (1H, d, J=5.48 Hz), 4.21 (3H, s), 3.83 (3H, s),3.83 (2H, s). MS (m/z) 576.2 (M+H).

Step 5a.N-(3-Fluoro-4-(2-(5-(hydroxymethyl)-1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(124)

Following the procedure described above for the synthesis of compound13a (example 12, step 3, scheme 2) but substituting compound 12 forcompound 122, title compound 124 was obtained as a beige solid (32 mg,39% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.48 (1H, s), 11.82 (1H, s),8.58 (1H, dd, 5.48, 0.98 Hz), 8.13 (1H, d, J=0.98 Hz), 8.03 (1H, d,J=12.52 Hz), 7.81 (1H, d, J=1.17 Hz), 7.55-7.54 (2H, m), 7.36-7.31 (4H,m), 7.27 (1H, m), 6.74 (1H, d, J=5.48 Hz), 4.21 (3H, s), 3.83 (3H, s),3.83 (2H, s). MS (m/z) 576.2 (M+H).

Example 87N-(4-(2-(N,N-Diethylcarbamimidoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(130) Step 1. 7-Chlorothieno[3,2-b]pyridine-2-carbaldehyde oxime (125)

To a solution of aldehyde 14 (scheme 3) in MeOH was added NH₂OH×HCl (227mg, 3.26 mmol) in water (0.5 mL) and the mixture was stirred at roomtemperature for 0.5 h. The solvents were removed by under reducedpressure and the residue was partitioned between EtOAc and water. Theorganic phase was dried over anhydrous sodium sulfate, filtered andevaporated to dryness to afford the title compound 125 (458 mg, 85%yield) as a white solid. MS (m/z) 213.1/215.1 (M+H).

Step 2. 7-Chlorothieno[3,2-b]pyridine-2-carbonitrile (126)

A solution of the oxime 125 (100 mg, 0.47 mmol) in acetic anhydride (2ml) was set to reflux for 3 h and then at 90° C. for 48 h. The aceticanhydride was removed under reduced pressure and the residue waspartitioned between a cold aqueous K₂CO₃ solution and EtOAc. The organicphase was dried over anhydrous sodium sulfate, concentrated to drynessand remained solid was purified by column chromatography, eluents 25%EtOAc/hexane (25:75), then 100% EtOAc, to afford the title compound 126(65 mg, 71% yield). MS (m/z) 195.1/197.1 (M+H).

Step 3. 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carbonitrile(127)

Following the procedure described above for the synthesis of compound 11(example 12, step 3, scheme 2) but substituting compound 10 for compound126, title compound 127 was obtained as a yellow solid (114 mg, 60%yield). MS (m/z) 316.0 (M+H).

Step 4.N,N-Diethyl-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboximidamide(128)

To a solution of nitrile 127 (116 mg, 0.37 mmol) in MeOH (3 mL) wasadded NaOMe (25% in MeOH, 0.09 ml, 0.39 mmol) and the mixture wasallowed to stir at room temperature for 18 h. Subsequently, Et₂NH×HCl(1.01 g, 9.25 mmol) was added and the mixture was heated to reflux for12 h., cooled to room temperature and the solvent was removed underreduced pressure. The residue was partitioned between EtOAc andsaturated aqueous ammonium chloride, the organic phase was dried overanhydrous sodium sulfate, filtered and concentrated to dryness. Theremained solid was purified by column chromatography (eluents EtOAc thenCHCl₃/MeOH/NH₄OH 44:5:0.5), to afford the title compound 128 (30 mg, 21%yield) as a white solid. MS (m/z) 389.2 (M+H).

Steps 4-5.N-(4-(2-(N,N-Diethylcarbamimidoyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(130)

Following the procedure described above for the synthesis of compound13a (example 12, steps 4-5, scheme 2) but substituting compound 11 forcompound 128 and using intermediate amine 129 (instead of amine 12),title compound 130 was obtained as a beige solid (5 mg, 13% yield). ¹HNMR (DMSO) δ (ppm): 8.58 (1H, d, J=5.48 Hz), 8.29 (1H, s), 8.02 (1H, d,J=11.35 Hz), 7.81 (1H, d, J=2.54 Hz), 7.53 (2H, br), 7.34-7.33 (5H, m),6.74 (1H, d, J=5.28 Hz), 3.83 (2H, s), 3.40 (4H, q, J=6.91 Hz), 1.16(6H, t, J=6.95 Hz). MS (m/z) 536.2 (M+H).

Example 88N-(3-Fluoro-4-(2-(morpholinomethyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(134) Step 1. 4-((7-Chlorothieno[3,2-b]pyridin-2-yl)methyl)morpholine(131)

To a solution of aldehyde 14 (scheme 3) (316 mg, 1.6 mmol) andmorpholine (0.15 ml, 1.52 mmol) in MeOH (20 mL) was added acetic acid(0.88 ml, 15 mmol), followed by sodium cyanoborohydride (105 mg, 1.67mmol). The resultant mixture was allowed to stir for 18 h, quenched withsaturated aqueous potassium carbonate solution (5 mL), evaporated underreduced pressure and the residue was partitioned between EtOAc andwater. The organic phase was dried over anhydrous sodium sulfate,concentrated to dryness and the remained solid was purified by columnchromatography, eluents EtOAc/hexane (30:70), then MeOH/EtOAc (1:99), toafford the title compound 131 (120 mg, 29% yield). MS (m/z) 269.0/271.0(M+H).

Step 2.4-((7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)methyl)morpholine(132)

Following the procedure described above for the synthesis of compound 11(example 12, step 3, scheme 2) but substituting compound 10 for compound131, title compound 132 was obtained as a yellow solid (110 mg, 69%yield). MS (m/z) 390.1 (M+H).

Steps 3-4.N-(3-Fluoro-4-(2-(morpholinomethyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(134)

Following the procedure described above for the synthesis of compound13a (example 12, steps 4-5, scheme 2) but substituting compound 11 forcompound 132 and using intermediate amine 133 (instead of amine 12),title compound 134 was obtained as a white solid (38 mg, 27% yield). ¹HNMR (DMSO) δ (ppm): 12.89 (1H, s), 12.24 (1H, s), 8.87 (1H, d, J=4.71Hz), 8.42 (1H, d, J=12.13 Hz), 7.95-7.88 (3H, m), 7.76-7.68 (5H, m),7.00 (1H, d, J=5.28 Hz), 4.26-4.25 (4H, m), 4.02 (4H, br), 3.76 (2H, s),2.90 (2H, s). MS (m/z) 537.2 (M+H).

Examples 89-92(S)-tert-Butyl1-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carbonyl)pyrrolidine-2-carboxylate(135a),(R)-tert-Butyl3-((7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxamido)methyl)pyrrolidine-1-carboxylate(135b),(R)—N-(4-(2-(3-(Dimethylamino)pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(135c), andN-(3-Fluoro-4-(2-(piperidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(135d)

Compounds 135a-d (examples 89-92) were obtained following the proceduresdescribed above for the synthesis of compound 8a (example 1, scheme 1).Characterization of 135a-d is provided in Table 11.

TABLE 11

Characterization of compounds 135a-d (examples 89-92) Cpd Ex R NameCharacterization 135a 89

(S)-tert-Butyl 1- (7-(2-fluoro-4-(3- (2-phenylacetyl)thioureido)phenoxy) thieno[3,2- b]pyridine-2- carbonyl)pyrrolidine-2-carboxylate 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.48(s, 1H), 11.82(s,1H), 8.61(d, J=5.6Hz, 0.7H), 8.58(d, J=5.6Hz, 0.3H), 8.10(s, 0.7H),8.03(bd, J=12.0Hz, 1H), 7.86(s, 0.3H), 7.57-7.51(m, 2H), 7.47-7.20(m,5H), 6.77(d, J=5.6Hz, 0.7H), 6.75(d, J=5.6Hz, 0.3H), 5.02-4.97(m, 0.3H),4.20(dd, J=3.2 and 8.4Hz, 0.7H), 3.97(t, J=6.8Hz, 1.4H), 3.82(s, 1.4H),3.80(t, J=6.8Hz, 0.6H), 3.55(s, 0.6H), 2.3-1.10(m, 5H), 1.41(s, 6.3H),1.19(s, 2.7H). 135b 90

(R)-tert-Butyl 3- ((7-(2-fluoro-4- (3-(2-phenylacetyl)thioureido)phenoxy) thieno[3,2- b]pyridine-2- carboxamido)methyl)pyrrolidine-1- carboxylate 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.48(s,1H), 11.81(s, 1H), 9.05-8.90(m, 1H), 8.58(d, J=5.6Hz, 1H), 8.32-8.22(m,1H), 8.02(d, J=11.6Hz, 1H), 7.56-7.52(m, 2H), 7.36-7.30(m, 4H),7.30-7.24(m, 1H), 6.73(d, J=5.6Hz, 1H), 4.00-3.90(m, 1H), 3.82(s, 2H),3.54-3.20(m, 4H), 1.91-1.74(m, 4H), 1.39(bs, 9H). 135c 91

(R)-N-(4-(2-(3- (Dimethylamino) pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin- 7-yloxy)-3-fluoro- phenylcarbamothioyl)-2-phenylacetamide 1H NMR (400 MHzCDCl3) δ ppm: 12.54(s, 1H), 8.80(s,1H), 8.54(d, 1H, J=5.5Hz), 8.14(s, 1H), 7.96(dd, 1H, J=11.4/2.1Hz),7.52-7.26(m, 6H), 6.63(d, 1H, J=5.5Hz), 4.35-3.52(m, 5H), 3.80(s, 2H),2.79(s, 6H), 2.70-2.40(m, 2H). 135d 92

N-(3-Fluoro-4-(2- (piperidine-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide LRMS(M+1) 549.3(100%),550.3(32%).

Example 93N-(3-Fluoro-4-(2-(piperidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (136a)

N-(3-Fluoro-4-(2-(piperidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(135d, example 92) (686 mg, 1.25 mmol) was solubilized in THF (2 mL);dichloromethane (4 mL) and 1M hydrogen chloride in ether (1.5 mL, 1.5mmol) were successfully added. The reaction mixture was stirred for 1hour, the solvents were partially evaporated under reduced pressure toform a precipitate, which was collected by filtration, to afford thetitle compound 136a (380 mg, 65% yield) as a light-yellow solid.Characterization of this material is provided in Table 12.

Example 94N-(3-Fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (136b)

Following the procedure described above for the synthesis of compound136a (example 93) but substituting compound 135d (example 92, table 11)for the compound 8o (example 37, table 6), title compound 136b wasobtained. Characterization of this material is provided in Table 12.

Example 95(S)-1-(7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carbonyl)pyrrolidine-2-carboxylicacid hydrochloride (136c)

Following the procedure described above for the synthesis of compound136a (Example 93) but substituting compound 135d (example 92, table 11)for the compound 135a (Example 89, Table 11), title compound 136c wasobtained. Characterization of this material is provided in Table 12.

Example 96N-(4-(2-(Azepane-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamidehydrochloride (136d)

Title compound 136d was obtained following the procedures describedabove for the synthesis of compound 136a (example 93, table 12).Characterization of 136d is provided in Table 12.

TABLE 12

Characterization of compounds 136a-d (examples 93-96) Cpd Ex R NameCharacterization 136a 93

N-(3-Fluoro-4-(2- (piperidine-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)phenyl- carbamothioyl)-2- phenylacetamide hydrochloride 1H NMR(400 MHzDMSO-d6) δ ppm: 12.49(s, 1H), 11.83(s, 1H), 8.65(d, 1H,J=5.7Hz), 8.05(d, 1H, J=11.3Hz), 7.82(s, 1H), 7.56-7.55(m, 2H),7.34-7.26(m, 5H), 6.84(d, 1H, J=5.7Hz), 3.83(s, 2H), 3.61-3.58(m, 4H),1.65-1.09(m, 6H). 136b 94

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)-2- phenylacetamide hydrochloride1H NMR (400 MHz, DMSO-d6) δ ppm: 12.49(s, 1H), 11.82(s, 1H), 8.64(d,J=5.6Hz, 1H), 8.08-8.01(m, 1H), 8.05(s, 1H), 7.58-7.53(m, 1H),7.36-7.31(m, 4H), 7.30-7.24(m, 1H), 6.82(d, J=5.6Hz, 1H), 3.85(t,J=6.4Hz, 2H), 3.82(s, 2H), 3.54(t, J=6.4Hz, 2H), 1.97(quin, J=6.4Hz,2H), 1.89(quin, J=6.4Hz, 2H). 136c 95

(S)-1-(7-(2-Fluoro-4- (3-(2-phenylacetyl) thioureido)phenoxy)thieno[3,2- b]pyridine-2- carbonyl)pyrrolidine- 2-carboxylic acidhydrochloride 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.49(s, 1H), 11.82(s,1H), 8.67(d, J=5.6Hz, 0.7H), 8.63(d, J=5.6Hz, 0.3H), 8.12(s, 0.7H),8.05(d, J=21.0Hz, 1H), 7.88(s, 0.3H), 7.58-7.54(m, 2H), 7.37-7.10(m,4H), 7.30-7.24(m, 1H), 6.85(d, J=5.6Hz, 0.7H), 6.81(d, J=5.6Hz, 0.3H),5.03-4.99(m, 0.3H), 4.48(dd, J=4.4 and 8.0Hz, 0.7H), 3.98(t, J=7.2Hz,1.4H), 3.82(s, 2H), 3.68-3.60(m, 0.6H), 2.32-2.25(m, 1H), 2.08-1.90(m,3H). 136d 96

N-(4-(2-(Azepane-1- carbonyl)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)- 2-phenylacetamide hydrochloride 1H NMR (400MHzDMSO-d6) δ ppm: 12.49(s, 1H), 11.83(s, 1H), 8.64(d, 1H, J=5.7Hz),8.04(d, 1H, J=11.5Hz), 7.85(s, 1H), 7.56-7.55(m, 2H), 7.34-7.26(m, 5H),6.81(d, 1H, J=5.5Hz), 3.83(s, 2H), 3.67-3.56(m, 4H), 1.76-1.57(m, 8H).

Example 97(S)-7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(pyrrolidin-3-ylmethyl)thieno[3,2-b]pyridine-2-carboxamidehydrochloride (137a)

To a solution of 135b (table 11) (16 mg, 0.028 mmol) in CH₂Cl₂ (15 mL)was added TFA (1 mL). The reaction mixture was stirred at roomtemperature until the reaction is complete, then the reaction mixturewas quenched with saturated aqueous sodium bicarbonate solution aextracted with DCM. The extract was concentrated, the residue wasdissolved in DCM (15 mL) and hydrogen chloride (0.5M in ether, 46 μL,0.046 mmol) was added. The reaction mixture was stirred for one hour,the solvents were partially evaporated under reduced pressure to form aprecipitate, which was collected by filtration, to afford the titlecompound 137a (10 mg, 87% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 12.48(s, 1H), 11.82(s, 1H), 9.49-9.43(m, 1H), 9.24(bs,1H), 8.74(bs, 1H), 8.62(d, J=5.6 Hz, 1H), 8.38(s, 1H), 8.03(d, J=12.0Hz, 1H), 7.58-7.5(m, 2H), 7.3-7.30(m, 4H), 7.30-7.24(m, 1H), 6.79(d,J=5.6 Hz, 1H), 3.80-3.54(m, 3H), 3.30-3.20(m, 1H), 3.20-3.10(m, 1H),2.12-2.02(m, 1H), 2.00-1.95(m, 2H), 1.74-1.63(m, 1H).

Example 987-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(2-(methylamino)ethyl)thieno[3,2-b]pyridine-2-carboxamide hydrochloride (137b) Steps 1-7.tert-Butyl2-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2b]pyridine-2-carboxamido)ethyl(methyl)carbamate(138)

Following the procedures described above for the synthesis of compound8a (Example 1, scheme 1) but replacing dimethyl amine with tert-butyl2-aminoethyl(methyl)carbamate, title compound 138 was obtained (13%).LRMS (M+1) 638.2 (100%).

Step 8.7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(2-(methylamino)ethyl)thieno[3,2-b]pyridine-2-carboxamide hydrochloride (137b)

Following the procedure described above for the synthesis of 137a butreplacing compound 135b with compound 138, title compound 137b wasobtained as an HCl salt in 65% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.49(s, 1H), 11.83(s, 1H), 9.39(t, J=5.2 Hz, 1H), 8.80(bs, 1H), 8.62(d,J=5.6 Hz, 1H), 8.39(s, 1H), 8.04(d, J=11.6 Hz, 1H), 7.97(bs, 1H),7.58-7.50(m, 2H), 7.37-7.31(m, 4H), 7.31-7.24(m, 1H), 6.80(d, J=5.6 Hz,1H), 3.78-3.71(m, 0.5H), 3.61(q, J=6.0 Hz, 1H), 3.21-3.24(m, 0.5H),3.18-3.04(m, 2H), 2.60(t, J=4.8 Hz, 2H).

Examples 99 and 100N-(3,5-Dichloro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(142) and7-(2,6-dichloro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-4-iumchloride (143) Steps 1-4.(7-Chlorothieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone (139)

Following the procedures described above for the synthesis of compound 5(scheme 1, example 1) but replacing dimethyl amine in the step 4 forpyrrolidine, title compound 139 was obtained. LRMS (M+1) 267.1 (100%).

Step 5.(7-(2,6-Dichloro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone(140)

Starting from the compound 139 and following the procedure describedabove for the synthesis of compound 6 (scheme 1, example 1) butreplacing 2-fluoro-4-nitrophenol with 2,6-dichloro-4-nitrophenol, titlecompound 140 was obtained in 69% yield. LRMS (M+1) 438.0 (100%), 439.1(20%), 440.1 (70%).

Steps 6-7.N-(3,5-Dichloro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(142)

Starting from the nitro compound 140 and following the proceduresdescribed above for the synthesis of 8a (steps 6-7, scheme 1, example 1)title compound 142 was obtained in 49% yield. LRMS (M+1) 585.3 (100%),586.2 (34%), 587.3 (72%).

7-(2,6-Dichloro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-4-iumchloride (143)

Following the procedure described above for the synthesis of compound136a (Table 12, Example 93) but replacing compound 135d with compound142, title compound 143 was obtained in 42% yield. Characterization of143 is provided in the Table 13.

Examples 101 and 102N-(3-Chloro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (144) andN-(3-Methyl-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (145)

Compounds 144-145 (examples 101-102) were obtained following theprocedures described above for the synthesis of compound 143 (example100). Characterization of compounds 144-145 is provided in the Table 13.

Examples 103 and 1042-Phenyl-N-(4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(146) andN-(3-(Dimethylamino)-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(147)

Compounds 146-147 (Examples 103-104) were obtained following theprocedures described above for the synthesis of compound 142 (Example99). Characterization of compounds 145-147 is provided in the Table 13.

TABLE 13

Characterization of compounds 143-146 (examples 99-103) Cpd Ex Ar NameCharacterization 143 100

N-(3,5-Dichloro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide hydrochloride¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.44(s, 1H), 11.91(s, 1H), 8.61(d, 1H,J=5.5Hz), 8.10(s, 2H), 8.06(s, 1H), 7.34-7.27(m, 5H), 6.68(d, 1H,J=5.5Hz), 3.88-3.83(m, 4H), 3.70-3.40(m, 2H), 1.99-1.18(m, 4H). 144 101

N-(3-Chloro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide hydrochloride¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.43(s, 1H), 11.83(s, 1H), 8.65(d, 1H,J=5.7Hz), 8.14(d, 1H, J=2.3Hz), 8.06(s, 1H), 7.70(dd, 1H, J=8.8/2.5Hz),7.55(d, 1H, J=8.8Hz), 7.34-7.26(m, 5H), 6.74(d, 1H, J=5.7Hz),3.87-3.83(m, 4H), 3.56-3.53(m, 2H), 1.99-1.88(m, 4H). 145 102

N-(3-Methyl-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide hydrochloride¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.43(s, 1H), 11.74(s, 1H), 8.62(d, 1H,J=5.7Hz), 8.04(s, 1H), 7.69-7.65(m, 2H), 7.43-7.26(m, 6H), 6.67(d, 1H,J=5.7Hz), 3.87-3.82(m, 4H), 3.67-3.38(m, 2H), 2.13(s, 3H), 1.99-1.18(m,4H). 146 103

2-Phenyl-N-(4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl) acetamide ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 12.41(s, 1H), 11.75(s, 1H), 8.68(d, J=5.6Hz, 1H),8.06(s, 1H), 7.77(d, J=8.8Hz, 2H), 7.36(d, J=8.8Hz, 2H), 7.34-7.31(m,4H), 7.30-7.24(m, 1H), 6.85(d, J=5.6Hz, 1H), 3.84(t, J=6.4Hz, 2H),3.82(s, 2H), 3.54(t, J=6.4Hz, 2H), 1.97(quin, J=6.4Hz, 2H), 1.89(quin,J=6.4Hz, 2H). 147 104

N-(3-(Dimethylamino)- 4-(2-(pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, CDCl₃) δ ppm: 8.48(d, 1H, J=6.1Hz), 8.27(s, 1H), 7.56(m, 8H),6.67(m, 1H), 3.91(t, 2H, J=6.8Hz), 3.78(s, 2H), 3.74(t, 2H, J=6.8Hz),2.73(s, 6H), 2.19-2.01(m, 4H).

Example 105N-(3-Fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(152a) Step 1. 4-Chloro-6-(tributylstannyl)thieno[3,2-d]pyrimidine (148)

Starting from 4-chloro-thieno[3,2-d]pyrimidine (20, scheme 4) andfollowing the procedure described above for the synthesis of tributyltincompound 98 (scheme 19), title compound 148 was obtained in 79% yield.LRMS (M+1) 461.1 (100%).

Step 2. 4-Chloro-6-(thiazol-2-yl)thieno[3,2-d]pyrimidine (149)

Starting from the tributyltin compound 148 and following the proceduredescribed above for the synthesis of compound 10 (scheme 2, example 12),title compound 149 was obtained in 81% yield. LRMS (M+1) 254.0 (100%).

Step 3.4-(2-Fluoro-4-nitrophenoxy)-6-(thiazol-2-yl)thieno[3,2-d]pyrimidine(150)

Starting from the bis-aryl compound 149 and following the proceduredescribed above for the synthesis of compound 11 (scheme 2, example 12)title compound 150 was obtained in 65% yield. LRMS (M+1) 375.0 (100%).

Steps 4-5.N-(3-Fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(152a)

Starting from the nitro compound 150, following the procedure describedabove for the synthesis of compound 13a (via the intermediate amine 12,scheme 2, example 12), title compound 152a was obtained [viaintermediate3-fluoro-4-(6-(thiazol-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine(151)] in 7% yield. Characterization of 152a is provided in the Table14.

Examples 106-108N-(3-Fluoro-4-(6-(pyridin-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(152b),N-(3-Fluoro-4-(6-(thiophen-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(152c), andN-(3-Fluoro-4-(6-(thiophen-2-yl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(152d)

Compounds 152b-d (Examples 106-108) were synthesized according to theScheme 27, similarly to the compound 152a (Example 105).Characterization of 152b-d is provided in the Table 14.

TABLE 14 Characterization of Compounds 152a-d (Examples 105-108) Cpd ExR Name Characterization 152a 105

N-(3-Fluoro-4-(6- (thiazol-2-yl) thieno[3,2-d] pyrimidin-4-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:8.75(s, 1H), 8.32(s, 1H), 8.05(d, J=3.2Hz, 1H), 8.03(d, J=3.2Hz, 1H),7.96-7.88(m, 1H), 7.58-7.50(m, 1H), 7.50-7.43(m, 1H), 7.36-7.30(m, 4H),7.30-7.23(m, 1H), 3.83(s, 2H). 152b 106

N-(3-Fluoro-4-(6- (pyridin-2-yl) thieno[3,2-d] pyrimidin-4-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.44(s, 1H), 11.80(s, 1H), 8.73(s, 1H), 8.70-8.64(m, 1H), 8.47(s, 1H),8.38(m, J=8.0Hz, 1H), 8.00(td, J=2.0 and 8.0Hz, 1H), 7.92(dd, J=2.0 and12.0Hz, 1H), 7.55(t, J=8.8Hz, 1H), 7.53-7.46(m, 2H), 7.36-7.31(m, 4H),7.30-7.24(m, 1H), 3.82(s, 2H). 152c 107

N-(3-Fluoro-4-(6- (thiophen-2-yl) thieno[3,2-d] pyrimidin-4-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.42(s, 1H), 11.80(s, 1H), 8.69(s, 1H), 7.92(dd, J=2.4 and 10.4Hz, 1H),7.91(s, 1H), 7.82(dd, J=1.2 and 4.8Hz, 1H), 7.79(dd, J=1.2 and 3.6Hz,1H), 7.54(t, J=8.8Hz, 1H), 7.47(dd, J=2.4 and 8.8Hz, 1H), 7.36-7.30(m,4H), 7.30-7.25(m, 1H), 7.24(dd, J=3.6 and 4.8Hz, 1H), 3.82(s, 2H). 152d108

N-(3-Fluoro-4-(6- (pyrimidin-2-yl) thieno[3,2-d] pyrimidin-4-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.44(s, 1H), 11.80(s, 1H), 9.00(s, 1H), 8.98(s, 1H), 8.77(s, 1H),8.37(s, 1H), 7.94(dd, J=2.4 and 12.0Hz), 7.61(t, J=5.2Hz, 1H), 7.57(t,J=8.8Hz, 1H), 7.49(dd, J=2.4 and 8.8Hz, 1H), 7.38-7.31(m, 4H),7.30-7.25(m 1H), 3.83(s, 2H).

Example 109N-(3-Fluoro-4-(2-(4-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155a) Step 1.4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (153)

To a solution of2-bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (42, scheme 8)(650 mg, 1.76 mmol) in ethylene glycol dimethyl ether (18 mL) were added4-hydroxyphenylboronic acid (486 mg, 3.52 mmol),tetrakis-triphenylphosphine palladium(0) (203 mg, 0.18 mmol), cesiumfluoride (802 mg, 5.28 mmol) and a solution of sodium bicarbonate (444mg, 5.28 mmol) in water (1 mL). The reaction mixture was purged withnitrogen, heated at 80° C. for 4 hours, quenched with saturated aqueousammonium chloride and extracted with EtOAc. The extract was washed withwater and brine, dried over anhydrous magnesium sulfate, filtered andevaporated under reduced pressure. The residue was purified bytrituration with methanol and ether to afford title compound 153 (418mg, 62% yield) as a yellow solid. LRMS (M+1) 383.1 (100%).

Step 2. 4-(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenol(154)

Following the procedure described above for the synthesis of the amine49 (scheme 10, example 55) but substituting nitro compound 48 for thenitro compound 153, title compound 154 was obtained in 99% yield (crudematerial, used in the next step without additional purification). LRMS(M+1) 353.1 (100%).

Step 3.N-(3-Fluoro-4-(2-(4-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155a)

Following the procedure described above for the synthesis of Compound 50(Scheme 10, Example 55) but substituting amine 49 for the amine 154,title Compound 155a was obtained in 3% yield. Characterization of 155ais provided in the Table 14a.

Examples 110-118N-(3-Fluoro-4-(2-(4-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155b)N-(3-Fluoro-4-(2-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155c)N-(3-Fluoro-4-(2-(3-fluoro-4-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155d)N-(3-Fluoro-4-(2-(4-morpholinophenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155e)N-(3-Fluoro-4-(2-phenylthieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155f)N-(3-Fluoro-4-(2-(2-morpholinopyrimidin-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155 g)N-(3-Fluoro-4-(2-(2-(2-morpholinoethoxy)pyrimidin-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155h)N-(3-Fluoro-4-(2-(2-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155i) andN-(3-Fluoro-4-(2-(4-hydroxy-3-methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155j)

Compounds 155b-j (Examples 110-118) were prepared similarly to theCompound 155a (Example 109, Scheme 28). Characterization of 155b-j isprovided in the Table 14a.

TABLE 14a

Characterization of compounds 152a-j (examples 109-118) Cpd Ex R NameCharacterization 155a 109

N-(3-Fluoro-4-(2-(4- hydroxyphenyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.46(s, 1H), 11.82(s, 1H), 9.95(s, 1H), 8.46(d, 1H, J=5.3Hz), 7.99(d,1H, J=13.1Hz), 7.83(s, 1H), 7.70(d, 2H, J=13.1Hz), 7.52-7.51(m, 2H),7.34-7.27(m, 5H), 6.86(d, 2H, J=8.6Hz), 6.59(d, 1H, J=5.5Hz), 3.83(s,2H). 155b 110

N-(3-Fluoro-4-(2-(4- methoxyphenyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.46(s, 1H), 11.82(s, 1H), 8.48(d, J=5.6Hz, 1H), 8.00(d, J=7.6Hz, 1H),7.91(s, 1H), 7.81(d, J=8.8Hz, 2H), 7.66-7.60(m, 2H), 7.37-7.31(m, 4H),7.31-7.24(m, 1H), 7.05(d, J=8.8Hz, 2H), 6.61(d, J=5.6Hz, 1H), 3.82(s,3H). 155c 111

N-(3-Fluoro-4-(2-(3- methoxyphenyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.46(s, 1H), 11.82(s, 1H), 8.52(d, J=5.6Hz, 1H), 8.10(s, 1H), 8.01(d,J=12.4Hz, 1H), 7.56-7.51(m, 2H), 7.46-7.37(m, 3H), 7.37-7.31(m, 4H),7.31-7.24(m, 1H), 7.05-7.00(m, 1H), 6.65(d, J=5.6Hz, 1H), 3.85(s, 3H),3.82(s, 2H). 155d 112

N-(3-Fluoro-4-(2-(3- fluoro-4- methoxyphenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s, H), 8.49(d, J=5.6Hz, 1H),8.01(s, 1H), 8.2-7.76(m, 1H), 7.84(dd, J=2.4 and 12.0Hz, 1H),7.66-7.61(m, 1H), 7.55-7.51(m, 2H), 7.38-7.10(m, 6H), 6.63(d, J=5.6Hz,1H), 3.90(s, 3H), 3.82(s, 2H). 155e 113

N-(3-Fluoro-4-(2-(4- morpholinophenyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.49(s, 1H), 11.85(s, 1H), 8.63(d, J=5.6Hz, 1H), 8.03(d, J=11.6Hz, 1H),7.89(s, 1H), 7.79(d, J=8.8Hz, 2H), 7.63-7.56(m, 2H), 7.36-7.31(m, 4H),7.31-7.25(m, 1H), 7.05(d, J=8.8Hz, 2H), 6.87(d, J=5.6Hz, 1H), 3.83(s,2H), 3.78-3.73(m, 4H), 3.30-3.24(m, 4H). 155f 114

N-(3-Fluoro-4-(2- phenylthieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.46(s, H), 11.82(s, 1H), 8.52(d, J=5.6Hz, 1H), 8.06(s, 1H), 8.01(d,J=12.4hz, 1H), 7.88(d, J=6.8Hz, 2H), 7.58-7.41(m, 5H), 7.38-7.31(m, 4H),7.31-7.24(m, 1H), 6.65(d, J=5.6Hz, 1H), 3.82(s, 2H). 155g 115

N-(3-Fluoro-4-(2-(2- morpholinopyrimidin-5- yl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s, 1H), 8.89(s, 2H), 8.49(d,J=5.6hz, 1H), 8.00(d, J=12.0Hz, 1H), 7.98(s, 1H), 7.56-7.51(m, 2H),7.37-7.31(m, 4H), 7.31-7.24(m, 1H), 6.61(d, J=5.6Hz, 1H), 3.82(s, 2H),3.82-3.76(m, 4H), 3.70-3.66(m, 4H). 155h 116

N-(3-Fluoro-4-(2-(2-(2- morpholinoethoxy) pyrimidin-5-yl)thieno[3,2-b]pyridin-7- yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 12.49(s, 1H), 11.85(s, 1H), 9.13(s, 2H),8.56(d, J=5.6Hz, 1H), 8.18(s, 1H), 8.03(d, J=1.8Hz, 1H), 7.60-7.54(m,2H), 7.39-7.32(m, 4H), 7.32-7.25(m, 1H), 6.68(d, J=5.6Hz, 1H), 4.50(t,J=5.6Hz, 2H), 3.83(s, 2H), 3.57(t, J=4.4Hz, 4H), 2.73(t, J=5.6Hz, 2H),2.51-2.44(m, 4H). 155i 117

N-(3-Fluoro-4-(2-(2- methoxyphenyl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.51(s, 1H), 11.84(s, 1H), 8.67(d, 1H, J=6.1Hz), 8.13(s, 1H), 8.08(d,1H, J=13.1Hz), 8.02(dd, 1H, J=7.7/1.5Hz), 7.61-7.60(m, 2H), 7.50(td, 1H,J=7.8/1.7Hz), 7.35-7.32(m, 4H), 7.29-7.26(m, 2H), 7.13(td, 1H,J=7.6/1.1Hz), 6.88(d, 1H, J=6.1Hz),4.00(s, 3H), 3.83(s, 2H). 155j 118

N-(3-Fluoro-4-(2-(4- hydroxy-3-methoxyphenyl) thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.49(s, 1H), 11.85(s, 1H), 9.57(s, 1H), 8.49(d,1H, J=5.5Hz), 8.01(d, 1H, J=13.5Hz), 7.94(s, 1H), 7.54-7.53(m, 2H),7.44(d, 1H, J=2.3Hz), 7.38-7.27(m, 6H), 6.88(d, 1H, J=8.2Hz), 6.61(d,1H, J=4.9Hz), 3.89(s, 3H), 3.83(s, 2H).

Example 119N-(3-Fluoro-4-(2-(2-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(155k)

To a cold (−40° C.) solution of the compound 155i (80 mg, 0.15 mmol) inDCM (3 mL) was added tribromoborane (1M in DCM, 0.60 mL, 0.60 mmol). Thereaction mixture was stirred overnight at room temperature. Water andmethanol were added and the mixture was stirred for additional 20minutes. Organic phase was separated and the aqueous layer was extractedwith EtOAc. Both organic phases were combined, washed with water andbrine, dried over anhydrous magnesium sulfate, filtered and evaporatedunder reduced pressure. The residue was purified by flash chromatography(eluent MeOH-DCM, 2:98) then triturated with methanol, to afford thetitle compound 155k (6 mg, 7%yield), as a light yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 12.47 (d, 1H, J=0.4 Hz), 11.82 (s, 1H), 10.65(s, 1H), 8.48 (d, 1H, J=5.5 Hz), 8.07 (s, 1H), 8.01 (d, 1H, J=l 1.5 Hz),7.84 (d, 1H, J=7.8 Hz), 7.53-7.49 (m, 2H), 7.38-7.23 (m, 6H), 7.01 (d,1H, J=8.2 Hz), 6.93 (t, 1H, J=7.4 Hz), 6.58 (d, 1H, J=5.5 Hz), 3.83 (s,2H). LRMS (M+1) 530.2 (100%).

Example 120N-(3-Fluoro-4-(2-(3-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(1551)

Following the procedure described above for the synthesis of compound155k (example 119, scheme 29) but substituting methoxy-compound 155i forthe methoxy-compound 155c, title compound 1551 was prepared in 62%yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.49(s, 1H), 11.84(s, 1H),8.68(d, J=5.6 Hz, 1H), 8.07(d, J=12.0 Hz, 1H), 7.99(s, 1H), 7.64-7.56(m,2H), 7.38-7.24(m, 8H), 6.96-6.88(m, 2H), 3.83(s, 2H).

Example 121N-(3-Fluoro-4-(2-(4-(piperazin-1-yl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidedi-hydro chloride (159) Step 1. tert-Butyl4-(4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate(156)

Starting from the nitro-bromo compound 42, following the proceduredescribed above for the synthesis of compound 48 (scheme 10, example 55)but substituting4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane for4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenylboronic acid, titlecompound 156 was obtained in 70% yield. LRMS (M+1) 550.6 (100%).

Step 2. tert-Butyl4-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)piperazine-1-carboxylate(157)

Following the procedure described above for the synthesis of amine 49(scheme 10, example 55) but substituting nitro compound 48 for the nitrocompound 156, title compound 157 was obtained in 99% yield (crudematerial, used in the next step without additional purification). LRMS(M+1) 520.2 (100%).

Step 3. tert-Butyl4-(4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-yl)phenyl)piperazine-1-carboxylate(158)

Following the procedure described above for the synthesis of compound 50(scheme 10, example 55) but substituting amine 49 for the amine 157,title compound 158 was obtained in 41% yield. LRMS (M+1) 697.2 (100%).

Step 4.N-(3-Fluoro-4-(2-(4-(piperazin-1-yl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidedi-hydrochloride (159)

Following the procedure described above for the synthesis of compound137a (scheme 25, example 97) but substituting compound 135b for thecompound 158, title compound 159 was obtained in 21% yield. ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.48(s, 1H), 11.84(s, 1H), 9.26(bs, 1H), 8.62(d,J=5.6 Hz, 1H), 8.05(d, J=12.0 Hz, 1H), 7.94(s, 1H), 7.81(d, J=8.8 Hz,2H), 7.62-7.55(m, 2H), 7.37-7.31(m, 4H), 7.31-7.24(m, 1H), 7.10(d, J=8.8Hz, 2H), 6.85(d, J=5.6 Hz, 1H), 3.83(s, 2H), 3.58-3.51(m, 4H),3.26-3.18(m, 4H). LRMS (M+1) 597.2 (100%).

Example 122N-(3-Fluoro-4-(2-(3-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163a) Step 1.3-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (160)

Starting from the nitrobromo compound 42, following the proceduredescribed above for the synthesis of compound 153 (scheme 28, example109) but substituting 4-hydroxyphenylboronic acid for3-hydroxyphenylboronic acid, title compound 160 was obtained in 66%yield as a gray solid. LRMS (M+1) 383.1 (100%).

Step 2.4-(2-(3-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)ethyl)morpholine(161)

Diethylazodicarboxylate (0.6 mL, 3.84 mmol) was added to the solution of160 (1.05 g, 2.75 mmol), 2-morpholinoethanol (0.5 mL, 3.84 mmol) andtriphenylphosphine (1.01 g, 3.84 mmol) in tetrahydrofuran (27 mL). Thereaction mixture was stirred until its completion, quenched withsaturated aqueous ammonium chloride and extracted with EtOAc. Theorganic phase was washed with water and brine, dried over anhydrousmagnesium sulfate, filtred and evaporated under reduced pressure. Theresidue was purified by flash chromatography, eluent MeOH-DCM (2:98) toafford title compound 161 (906 mg, 66%yield) as a light-yellow solid.LRMS (M+1) 496.3 (100%).

Step 3.3-Fluoro-4-(2-(3-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(162)

Following the procedure described above for the synthesis of amine 49(scheme 10, example 55) but substituting nitro compound 48 for the nitrocompound 161, title compound 162 was obtained in 91% yield (crudematerial, used in the next step without additional purification). LRMS(M+1) 466.2 (100%).

Step 4.N-(3-Fluoro-4-(2-(3-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163a)

Following the procedure described above for the synthesis of compound 50(scheme 10, example 55) but substituting amine 49 for the amine 162,title compound 163a was obtained in 29% yield. Characterization of 163ais provided in the table 15.[LRMS (M+1) 643.3 (100%).

Examples 123-127N-(3-Fluoro-4-(2-(4-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163b)N-(3-Fluoro-4-(2-(4-(2-(piperidin-1-yl)ethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163c)N-(3-Fluoro-4-(2-(4-(2-(pyridin-2-yl)ethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (163d)N-(3-Fluoro-4-(2-(4-(3-morpholinopropoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163e) tert-Butyl2-(4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)ethyl(methyl)carbamate(163f)

Starting from the phenol 153 (scheme 28, example 109) and following theprocedures described above for the synthesis of 163a (Scheme 31, Example122) title compounds 163b-f were obtained. Characterization of 163b-f isprovided in the Table 15.

Examples 128-129N-(3-Fluoro-4-(2-(3-methoxy-4-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(163g)N-(3-Fluoro-4-(2-(2-(2-morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidehydrochloride (163h)

Following the procedures described above for the synthesis of 163a(Scheme 31, example 122) but replacing in the first step3-hydroxyphenylboronic acid with 4-hydroxy-3-methoxyphenylboronic acidor 2-hydroxyphenylboronic acid, title compounds 163g-h were obtained.Characterization of 163g-h is provided in the table 15.

TABLE 15

Characterization of compounds 163a-h (examples 122-128) Cpd Ex R NameCharacterization 163a 122

N-(3-Fluoro-4- (2-(3-(2- morpholinoethoxy) phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.47(s, 1H), 11.82(s, 1H), 8.52(d, 1H, J=5.5Hz),8.12(s, 1H), 8.01(d, 1H, J=12.1Hz), 7.54-7.52(m, 2H), 7.45-7.26(m, 8H),7.04-7.01(m, 1H), 6.65(d, 1H, J=5.3Hz), 4.20(t, 2H, J=5.8Hz), 3.83(s,2H), 3.57(t, 4H, J=4.6Hz), 2.73(t, 2H,J=5.6Hz), 2.51-2.49(m, 4H). 163b123

N-(3-Fluoro-4- (2-(4-(2- morpholinoethoxy) phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s, 1H), 8.49(s, J=5.6Hz, 1H),8.00(d, J=12.0Hz, 1H), 7.94(s, 1H), 7.90-7.78(m, 2H), 7.56-7.38(m, 2H),7.39-7.22(m, 5H), 7.16-7.02(m, 2H), 6.62(d, J=5.6H, 1H), 4.34-3.90(m,3H), 3.82(s, 2H), 3.76-2.40(m, 9H). 163c 124

N-(3-Fluoro-4-(2- (4-(2-(piperidin- 1-yl)ethoxy) phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 8.52(bs, 1H), 8.38(d, J=5.6Hz, 1H), 8.0(dd, J=2.0and 12.0Hz, 1H), 7.75(d, J=8.4Hz, 2H), 7.64(s, 1H), 7.44-7.40(m, 1H),7.38-7.29(m, 5H), 7.29-7.24(m, 1H), 7.07(d, J=8.4Hz, 2H), 6.60(d,J=5.6Hz, 1H), 4.39-4.31(m, 2H), 3.75(s, 2H), 3.39-3.33(m, 2H),3.20-3.05(m, 4H), 1.89-1.79(m, 4H), 1.70-1.60(m, 2H). 163d 125

N-(3-Fluoro-4- (2-(4-(2-(pyridin-2- yl)ethoxy)phenyl) thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide hydrochloride¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.48(s, 1H), 11.84(s, 1H), 8.81(d,J=4.8Hz, 1H), 8.61(d, J=5.6Hz, 1H), 8.44(t, J=7.6Hz, 1H), 8.35-7.98(m,2H), 7.97(s, 1H), 7.86(d, J=8.8Hz, 2H), 7.61-7.55(m, 2H), 7.38-7.31(m,4H), 7.31-7.24(m, 1H), 7.07(d, J=8.8Hz, 2H), 6.82(d, J=5.6Hz, 1H),4.51(t, J=6.0Hz, 2H), 3.83(s, 2H), 3.52(t, J=6.0Hz, 2H). 163e 126

N-(3-Fluoro-4- (2-(4-(3- morpholinopropoxy) phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s, 1H), 8.48(d, 1H, J=5.3Hz),8.00(d, 1H, J=12.5Hz), 7.91(s, 1H), 7.80(d, 2H, J=8.8Hz), 7.53(m, 2H),7.34-7.22(m, 5H), 7.04(d, 2H, J=8.6Hz), 6.61(d, 1H, J=5.7Hz),4.10-4.07(m, 2H), 3.83(s, 2H), 3.59-3.55(m, 4H),2.50-2.41(m, 6H),1.92(m, 2H) 163f 127

tert-Butyl 2-(4- (7-(2-fluoro-4-(3- (2-phenylacetyl) thioureido)phenoxy)thieno[3,2- b]pyridin-2- yl)phenoxy)ethyl (methyl)carbamate ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 12.50(S, 1H), 11.85(s, 1H), 8.50(d, 1H,J=5.5Hz), 8.02(d, 1H, J=13.3Hz), 7.94(s, 1H), 7.83(d, 2H, J=8.8Hz),7.55-7.54(m, 2H), 7.38-7.26(m, 5H), 7.08(d, 2H, J=8.8Hz), 6.63(d, 1H,J=5.3Hz), 4.17(br s, 2H), 3.83(s, 2H),3.56(m, 2H), 2.90-2.86(m, 3H),1.40-1.36(m, 9H). 163g 128

N-(3-Fluoro-4-(2- (3-methoxy-4-(2- morpholinoethoxy) phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ ppm: 8.51(d, 1H, J=5.5Hz), 8.03-8.01(m, 2H),7.55-7.53(m, 2H), 7.47(d, 1H, J=2.2Hz), 7.39-7.24(m, 6H), 7.10(d, 1H,J=8.6Hz), 6.63(d, 1H, J=5.5Hz), 4.14(t, 2H, J=5.9Hz), 3.88(s, 3H),3.83(s, 2H), 3.58(t, 4H, J=4.6Hz), 2.71(t, 2H, J=5.9Hz), 2.46-2.43(m,4H). 163h 129

N-(3-Fluoro-4- (2-(2-(2- morpholinoethoxy) phenyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamide hydrochloride1H NMR (400 MHz, DMSO-d6) δ ppm: 12.50(s, 1H), 11.86(s, 1H),11.66-11.50(br s, 1H), 8.79-8.76(m, 1H), 8.37(d, 1H, J=5.9Hz), 8.08(dd,1H, J=11.3/2.0Hz), 7.93(dd, 1H, J=7.6/1.6Hz), 7.63-7.52(m, 3H),7.35-7.16(m, 7H), 6.99(t, 1H, J=4.8Hz), 4.71(br s, 2H), 3.93-3.91(m,2H), 3.84(s, 2H), 3.80-3.77(m, 4H), 3.53-3.50(m, 2H), 3.36-3.33(m, 2H).

Example 130N-(3-Fluoro-4-(2-(4-(piperidin-4-ylmethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(167a) Step 1.tert-Butyl-4-((4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)methyl)piperidine-1-carboxylate(164)

Starting from the compound 153 (shown in the scheme 28) and followingthe procedure described above for the synthesis of compound 161 (step 2,scheme 31, example 122), title compound 164 was obtained in 69% yield.LRMS (M+1) 579.2 (100%).

Step 2. tert-Butyl4-((4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)methyl)piperidine-1-carboxylate(165)

Following the procedure described above for the synthesis of amine 157(scheme 30, example 121) but substituting nitro compound 156 for thenitro compound 164, title compound 165 was obtained in 99% yield (crudematerial, used in the next step without additional purification). LRMS(M+1) 549.2 (100%).

Step 3.tert-Butyl-4-((4-(7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)methyl)piperidine-1-carboxylate(166)

Following the procedure described above for the synthesis of compound158 (scheme 30, example 121) but substituting amino compound 157 for theamino compound 165, title compound 166 was obtained in 31% yield. LRMS(M+1) 726.2 (100%).

Step 4.N-(3-Fluoro-4-(2-(4-(piperidin-4-ylmethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamidedi-hydrochloride (167a)

Following the procedure described above for the synthesis of compound159 (scheme 30, example 121) but substituting Boc-protected aminocompound 158 for the Boc-protected amino compound 166, title compound167a (presumably as a di-hydrochloride salt) was obtained in 15% yield.Characterization of 167a is provided in the table 16. LRMS (M+1) 626.2(100%).

Example 131-132(S)—N-(3-Fluoro-4-(2-(4-(pyrrolidin-2-ylmethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(167b) andN-(4-(2-(4-(4-Aminobutoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(167c)

Following the procedures described above for the synthesis of 167a(scheme 32, example 130) but replacing in the first step tert-butyl4-(hydroxymethyl)piperidine-1-carboxylate with(S)-tert-butyl2-(hydroxymethyl)pyrrolidine-1-carboxylate or tert-butyl4-hydroxybutylcarbamate, title compounds 167b-c were obtained.Characterization of 167b-c is provided in the table 16.

TABLE 16

Characterization of compounds 167a-c (examples 130-132) Cpd Ex X NameCharacterization 167a 130

N-(3-Fluoro-4-(2- (4-(piperidin-4- ylmethoxy)phenyl) thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamidedi-hydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.41(d, J=5.6hz, 1H),8.06(dd, J=3.2 and 12.4Hz, 1H), 7.75(d, J=8.8Hz, 2H), 7.65(s, 1H),7.37-7.43(m, 1H), 7.39(d, J=8.4Hz, 1H), 7.37-7.33(m, 4H), 7.33-7.25(m,1H), 7.04(d, J=8.8Hz, 2H), 6.64(d, J=5.6Hz, 1H), 3.98(d,J=5.6Hz, 2H),3.76(s, 2H), 3.50-3.42(m, 2H), 3.12-3.01(m, 2H), 2.25-2.16(m, 1H),2.162.06(m, 2H), 1.92-1.58(m, 2H). 167b 131

(S)-N-(3-Fluoro-4- (2-(4-(pyrrolidin-2- ylmethoxy)phenyl) thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-phenylacetamidedi-hydrochloride ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.46(s, 1H), 11.82(s,1H), 8.49(d, J=5.6Hz, 1H), 8.04-7.88(m, 1H), 7.96(s, 1H), 7.86(d,J=8.8Hz, 1H), 7.56-7.51(m, 2H), 7.36-7.31(m, 4H), 7.31-7.24(m, 1H),7.11(d, J=8.8Hz, 2H), 6.63(d, J=5.6Hz, 1H), 4.34(dd, J=4.4 and 10.8Hz,1H), 4.20-4.12(m, 1H), 4.00-3.90(m, 1H), 3.82(s, 2H), 3.28-3.18(m, 2H),2.20-2.10(m, 1H), 2.05-1.88(m, 2H), 1.82-1.70(m, 1H). 167c 132—O(CH₂)₄NH₂ N-(4-(2-(4-(4- ¹H NMR (400 MHz, DMSO-d₆) δAminobutoxy)phenyl) ppm: 8.40(d, J=5.6Hz, 1H), 8.05(dd, thieno[3,2-J=3.2 and 12.0Hz, 1H), 7.75(d, J=8.8Hz, b]pyridin-7-yloxy)-3- 2H),7.64(s, H), 7.48-7.43(m, 1H), fluorophenylcarbamothioyl)- 7.39(d,J=8.8Hz, 1H), 7.37-7.31(m, 4H), 2-phenylacetamide 7.31-7.24(m, 1H),7.03(d, J=8.8Hz, di-hydrochloride 2H), 6.64(d, j=5.6Hz, 1H), 4.11(t,J=5.6Hz, 2H), 3.76(s, 2H), 3.03(t, J=7.2Hz, 2H), 1.99-1.83(m, 4H).

Example 133N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(170a) Step 1. 7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (168)

Starting from the chloride 2 (scheme 1) and following the proceduredescribed above for the synthesis of compound 6 (scheme 1, example 1),title compound 168 was obtained in 45% yield. LRMS (M+1) 290.3 (100%).

Step. 3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)benzenamine (169)

Starting from the nitro compound 168 and following the proceduredescribed above for the synthesis of amine 49 (scheme 10, example 55),title compound 169 was obtained in 41% yield. LRMS (M+1) 260.3 (100%).

Step 3.N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(170a)

Starting from the amine 169 and following the procedure described abovefor the synthesis of compound 50 (scheme 10, example 55), title compound170a was obtained in 29 % yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm:12.46(s, 1H), 11.81(s, 1H), 8.52(d, J=5.2 Hz, 1H), 8.17(d, J=5.2 Hz,1H), 8.01(dd, J=2.0 and 11.2 Hz, 1H), 7.60(d, J=5.2 Hz, 1H),7.58-7.48(m, 2H), 7.36-7.30(m, 4H), 7.30-7.22(m, 1H), 6.64(d, J=5.2 Hz,1H), 3.82(s, 2H). LRMS (M+1) 437.5 (100%).

Example 134N-(2-Chloro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(170b)

Title compound 170b (example 134) was obtained according to the scheme33 via a 3-step synthesis starting from the chloride 2 and replacing2-fluoro-4-nitrophenol [in the step 1] with 3-chloro-4-nitrophenol. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 12.36(s, 1H), 11.88(s, 1H), 8.55(d, J=5.6Hz, 1H), 8.159d, J=5.6 Hz, 1H), 8.08(d, J=8.8 Hz, 1H), 7.61(d, J−2.8 Hz,1H), 7.60(d, J=5.6 Hz, 1H), 7.36-7.30(m, 4H), 7.32(m, J=2.8 Hz, 1H),7.30-7.24(m, 1H), 6.73(d, J=5.6 Hz, 1H), 3.84(s, 2H).

Example 135N-(2-Chloro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(173) Step 1. 4-(3-Chloro-4-nitrophenoxy)thieno[3,2-d]pyrimidine (171)

Starting from the chloride 20 (scheme 4) and following the proceduredescribed above for the synthesis of compound 24 (scheme 4, example 22)remplacing 2-fluoro-4-nitrophenol with 3-chloro-4-nitrophenol, titlecompound 171 was obtained in 72% yield. LRMS (M+1) 307.7 (100%).

Step 2. 2-Chloro-4-(thieno[3,2-d]pyrimidin-4-yloxy)benzenamine (172)

Starting from the nitro compound 171 and following the proceduredescribed above for the synthesis of amine 25 (scheme 4, example 22),title compound 172 was obtained in 80% yield. LRMS (M+1) 277.7 (100%).

Step 3.N-(2-Chloro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(173)

Starting from the amine 172 and following the procedure described abovefor the synthesis of compound 26a (scheme 4, example 22), title compound173 was obtained in 9% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.35(s,1H), 11.89(s, 1H), 8.72(s, 1H), 8.48(d, J=5.6 Hz, 1H), 8.04(d, J=8.8 Hz,1H), 7.69(d, J=2.8 Hz, 1H), 7.68(d, J=5.6 Hz, 1H), 7.40(dd, J=2.8 and8.8 Hz, 1H), 7.36-7.30(m, 4H), 7.30-7.24(m, 1H), 3.84(s, 2H). LRMS (M+1)(100%).

Example 1362-Phenyl-N-(2-(thieno[3,2-d]pyrimidin-4-ylamino)pyrimidin-5-ylcarbamothioyl)acetamide(174)

Title compound 174 (example 136) was obtained according to the scheme 34via a 3-step synthesis starting from the chloride 20 and replacing3-chloro-4-nitrophenol [in the step 1] with 5-nitropyrimidin-2-amine. ¹HNMR (400 MHz, DMSO-d₆) δ ppm: 11.85(bs, 2H), 10.91(bs, 1H), 8.71(s, 1H),8.64(s, 2H), 8.63-8.61(m, 1H), 8.25(d, J=5.6 Hz, 1H), 7.45(d, J=5.6 Hz,1H), 7.34-7.27(m, 4H), 7.27-7.21(m, 1H), 3.79(s, 2H).

Example 137N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-fluorophenyl)acetamide(178) Step 1.7-Chloro-2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (175)

To a solution of chloride 2 (scheme 1) (2.45 g, 14.4 mmol) in THF (48mL) at −78° C. was slowly added n-BuLi (2.5M in hexane, 7.2 mL, 18.0mmol). The reaction mixture was stirred for one hour [at −78° C.]followed by slow addition of ZnCl (0.5M in THF, 36 mL, 18.0 mmol). In afew minutes the reaction mixture was allowed to warm to room temperatureand stirred for one hour.

A solution of 4-iodo-1-methyl-1H-imidazole (1.50 g, 7.2 mmol) [Tet.Lett. 2004, 45, 5529] in THF (5 mL) and the tetrakis(triphenylphosphine)palladium (0) (0.83 g, 0.72 mmol) were added to the reaction mixturewhich was heated to reflux for 1 hour, cooled to room temperature,diluted with aqueous ammonium hydroxide and, finally neutralized with a1N HCl solution. The acidic solution was extracted with DCM, the extractwas washed with water and brine, dried over anhydrous magnesium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby flash chromatography (eluents DCM, then DCM-MeOH, 97:3) to affordtitle compound 175 (1.45 g, 81% yield) as a yellow solid. LRMS (M+1)263.9 (100%), 265.9 (33%).

Step 2. 7-(2-Fluoro-4-nitrophenoxy)-2-(l-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (176)

Starting from the chloride 175 and following the procedure describedabove for the synthesis of compound 11 (scheme 2, example 12), titlecompound 176 was obtained in 47% yield. LRMS (M+1) 371.0 (100%).

Step 3.3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(177)

Starting from the nitro compound 176 and following the proceduredescribed above for the synthesis of amine 49 (scheme 10, example 55),title compound 177 was obtained in 74% yield. LRMS (M+1) 341.0 (100%).

Step 4.N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-fluorophenyl)acetamide(178)

Starting from the amine 177, following the procedure described above forthe synthesis of compound 50 (scheme 10, example 55) but replacing2-phenylacetyl isothiocyanate with 2-(2-fluorophenyl)acetylisothiocyanate, title compound 178 was obtained in 24% yield. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 12.44 (s, 1H), 11.88 (s, 1H), 8.46 (d, 1H,J=5.5 Hz), 8.34 (dd, 1H, J=12.3/2.2 Hz), 7.87 (d, 1H, J=1.2 Hz), 7.72(d, 1H, J=1.2 Hz), 7.69 (s, 1H), 7.57-7.49 (m, 2H), 7.43-7.31 (m, 2H),7.23-7.15 (m, 2H), 6.59 (d, 1H, J=5.5 Hz), 3.94 (s, 2H), 3.73 (s, 3H).LRMS (M+1) 536.1 (100%).

Example 138N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(179)

Starting from the amine 177, following the procedure described above forthe synthesis of compound 50 (scheme 10, example 55) but replacing2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetylisothiocyanate, title compound 179 was obtained in 52% yield. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 12.58 (s, 1H), 11.75 (s, 1H), 8.46 (d, 1H,J=5.5 Hz), 8.72 (dd, 1H, J=12.3/2.2 Hz), 7.86 (d, 1H, J=1.2 Hz), 7.72(d, 1H, J=0.8 Hz), 7.70 (s, 1H), 7.57-7.49 (m, 2H), 7.30-7.23 (m, 2H),7.00 (d, 1H, J=7.8 Hz), 6.92 dt, 1H, J=7.3/0.9 Hz), 6.58 (d, 1H, J=5.1Hz), 3.82 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H).

Example 139N-(3-Fluoro-4-(2-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(184) Step 1. tert-Butyl2-(4-(7-chlorothieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(methyl)carbamate(180)

Starting from the chloride 2 and following the procedure described abovefor the synthesis of 175 (scheme 35, example 138), but replacing4-iodo-1-methyl-1H-imidazole with tert-butyl2-(4-iodo-1H-pyrazol-1-yl)ethyl(methyl)carbamate, title compound 180 wasobtained in 75% yield. LRMS (M+1) 393.1 (100%).

Step 2. tert-Butyl2-(4-(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(methyl)carbamate(181)

Starting from the chloride 180 and following the procedure describedabove for the synthesis of compound 11 (scheme 2, example 12), titlecompound 181 was obtained in 37% yield. LRMS (M+1) 514.1 (100%).

Step 3. tert-Butyl2-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1yl)ethyl(methyl)carbamate(182)

Starting from the nitro compound 181 and following the proceduredescribed above for the synthesis of amine 49 (scheme 10, example 55),title compound 182 was obtained in 22% yield. LRMS (M+1) 484.2 (100%).

Step 4. tert-Butyl2-(4-(7-(2-fluoro-4-(3-(2-(2-methoxyphenyl)acetyl)thioureido)phenoxy)thieno[3,2-b]pyridin-2-yl)-1H-pyrazol-1-yl)ethyl(methyl)carbamate(183)

Starting from the amine 182, following the procedure described above forthe synthesis of compound 50 (scheme 10, example 55) but replacing2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetylisothiocyanate, title compound 183 was obtained in 90% yield. LRMS (M+1)691.2 (100%).

Step 5.N-(3-Fluoro-4-(2-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(184)

Starting from the compound 183 and following the procedure describedabove for the synthesis of compound 159 (scheme 30, step 4, example121), title compound 184 was obtained in 66% yield. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 8.45(d, J=5.6 Hz, 1H), 8.33(s, 1H), 8.00(s, 1H),7.85-7.75(m, 1H), 7.69(s, 1H), 7.39(t, J=8.4 Hz, 1 H), 7.35-7.28(m, 1H),7.28-7.22(m, 1H), 7.22(d, J=7.6 Hz, 1H), 6.97(d, J=8.4 Hz, 1H), 6.89(t,J=7.6 Hz, 1H), 6.57(d, J=5.6 Hz, 1H), 4.19(t, J=6.4 Hz, 2H), 3.82(s,2H), 3.77(s, 3H), 2.88(t, J=6.4 Hz, 2H), 2.28(s, 3H).

Example 140N-(3-Fluoro-4-(2-(1-(2-morpholinoethyl)-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(185)

Title compound 185 (example 140) was obtained following the proceduresdescribed above for compound 183 [according to the scheme 36] via a4-step synthesis starting from chloride 2 and replacing tert-butyl2-(4-iodo-1H-pyrazol-1-yl)ethyl(methyl)carbamate [in the step 1] with4-(2-(4-iodo-1H-imidazol-1-yl)ethyl)morpholine [Tet. Lett. 2004, 45,5529]. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.56(s, 1H), 11.75(s, 1H),8.55(d, J=5.6 Hz, 1H), 8.50 -8.20(m, 1H), 7.93(d, J=1.2 Hz, 1H), 7.78(s,1H), 7.60-7.55(m, 2H), 7.35(d, J=1.2 Hz, 1H), 7.32-7.25(m, 1H), 7.23(dd,J=1.6 and 7.2 Hz, 1H), 7.00(d, J=7.6 Hz, 1H), 6.92(td, J=0.8 and 7.6 Hz,1H), 6.69(d, J=5.6 Hz, 1H), 4.35(t, J=6.0 Hz, 2H), 3.81(s, 2H), 3.78(s,3H), 3.48(t, J=4.4 Hz, 4H), 2.59(t, J=6.0 Hz, 2H), 2.35(t, J=4.4 Hz,4H).

Example 141N-(3-Fluoro-4-(6-(1-hydroxy-2-methylpropyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(190) Step 1. 4-Chloro-thieno[3,2-d]pyrimidine-6-carbaldehyde (186)

Starting from 4-chloro-thieno[3,2-d]pyrimidine (20, scheme 4) andfollowing procedure described above for the synthesis of aldehyde 14(scheme 3, step 1, example 20), title compound 186 was obtained in 84%yield. LRMS (M+1) 199.0 (100%).

Steps2-3.1-[4-(2-Fluoro-4-nitro-phenoxy)-thieno[3,2-d]pyrimidin-6-yl]-ethanol(188)

Starting from the aldehyde 186 and following procedures described abovefor the synthesis of nitro compound 16 (scheme 3, steps 2-3, example20), title compound 188 was obtained [via the intermediate alcohol 187],in 25% yield. LRMS (M+1) 336.0 (100%).

Steps 3-4.N-(3-Fluoro-4-(6-(1-hydroxy-2-methylpropyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(190)

Starting from the nitro compound 188 and following procedures describedabove for the synthesis of compound 18a (scheme 3, steps 4-5, example20), title compound 190 was obtained [via the intermediate amino alcohol189], in 24% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.42(s, 1H),11.80(s, 1H), 8.64(s, 1H), 7.90(dd, J=2.0 and 12.0 Hz, 1H), 7.52(t,J=H), 7.528.4 Hz, 1H), 7.48(d, J=0.8 Hz, 1H), 7.46(dd, J=2.0 and 8.4 Hz,1H), 7.36-7.31(m, 4H), 7.31-7.24(m, 1H), 6.15(d, 4.8 Hz, 1H), 4.82(td,J=0.8 and 5.2 Hz, 1H), 3.82(s, 1.98(m, 1H), 0.93(d, J=6.8 Hz, 3H),0.90(d, J=6.8 Hz, 3H).

Examples 142-148N-(3-Fluoro-4-(6-(pyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(26f)N-(4-(2-(Azetidine-1-carbonyl)thieno[3,2-b]□yridine-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamidehydrochloride (26 g)1-(4-(6-(N-Ethyl-N-methylcarbamoyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(26h)N,N-Diethyl-4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-d]pyrimidine-6-carboxamide(26i)(R)—N-(3-Fluoro-4-(6-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(26j)(S)—N-(4-(6-(3-(tert-Butyldimethylsilyloxy)pyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(26k) tert-Butyl1-(4-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-d]pyrimidine-6-carbonyl)pyrrolidin-3-ylcarbamate(261)

Compounds 26f-l (examples 142-148) were obtained by following theprocedures described above for the compound 26a (example 22, scheme 4).Characterization of 26f-l is provided in the table 17.

TABLE 17

Characterization of compounds 26f-l (examples 142-148) Cpd Ex R NameCharacterization 26f 142

N-(3-Fluoro-4-(6- (pyrrolidine-1- carbonyl)thieno[3,2-d]pyrimidin-4-yloxy) phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.79(s, 1H), 8.77(s, 1H), 8.11(s,1H), 7.92(dd, J = 2.0 and 11.6Hz, 1H), 7.54(t, J = 8.4Hz, 1H), 7.47(dd,J = 2.0 and 8.4Hz, 1H), 7.36-7.31(m, 4H), 7.30-7.32(m, 1H), 3.85(t, J =6.4Hz, 2H), 3.82(s, 2H), 3.55(t, J = 6.4Hz, 2H), 1.96(quin, J = 6.4Hz,2H), 1.89(quin, J = 6.4Hz, 2H). 26g 143

N-(4-(2-(Azetidine-1- carbonyl)thieno[3,2- b]pyridine-7- yloxy)-3-fluorophenylcarbamothioyl)- 2-phenylacetamide hydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.48(s, 1H), 11.82(s, 1H), 8.64(d, J = 5.6Hz,1H), 8.03(db, J = 12.8Hz, 1H), 7.91(s, 1H), 7.58-7.52(m, 2H),7.37-7.31(m, 4H), 7.30-7.24(m, 1H), 6.82(d, J = 5.6Hz, 1H), 4.62(t, J =7.2Hz, 2H), 4.11(t, J=7.2Hz, 2H), 3.82(s, 2H), 2.35(quin, J = 7.2Hz,2H). 26h 144

1-(4-(6-(N-Ethyl-N- methylcarbamoyl)thieno [3,2-d]pyrimidin- 4-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.44(s, 1H), 11.81(s, 1H), 8.77(s, 1H), 8.03(s, 1/2H), 7.93(dd,1H, J = 11.9/2.3Hz), 7.89(s, 1/2H), 7.54(t, 1H, J = 8.5Hz), 7.48(dd, 1H,J = 8.8/2.2Hz), 7.38-7.32(m, 4H), 7.30-7.25(m, 1H), 3.82(s, 2H), 3.52(m,2H), 3.23(s, 3/2H), 3.04(s, 3/2H), 1.19(m, 3H). 26i 145

N,N-Diethyl-4-(2- fluoro-4-(3-(2- phenylacetyl)thioureido)phenoxy)thieno[3,2- d]pyrimidine-6- carboxamide ¹H NMR (400 MHz,DMSO-d₆) δ (ppm): 12.44(s, 1H), 11.80(s, 1H), 8.77(s, 1/3H), 8.77(s,2/3H), 7.93(dd, 1H, J = 2.2/11.9Hz), 7.89(s, 1/3H), 7.89(s, 2/3H),7.54(t, 1H, J = 8.5Hz), 7.48(dd, 1H, J = 1.8/8.3Hz), 7.34-7.33(m, 4H),7.29-7.26(m, 1H), 3.83(s, 2H), 3.53-3.48(m, 4H), 1.21(m, 6H). 26j 146

®-N-(3-Fluoro-4-(6- (2-(hydroxymethyl) pyrrolidine-1-carbonyl)thieno[3,2- d]pyrimidin-4-yloxy) phenylcarbamothioyl)-2-phenylacetamide ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.41(s, 1H);11.80(s, 1H); 8.77(s, 1H); 8.08(s, 1H); 7.92(d, J = 11.6Hz, 1H); 7.54(t,J = 8.8Hz, 1H); 7.49-7.45(m, 1H); 7.34-7.26(m, 5H); 4.84(t, J = 4.4Hz,1H); 4.23-4.19(m, 1H); 3.91-3.78(m, 2H); 3.82(s, 2H); 3.62-3.51(m, 2H);2.07-1.87(m, 4H). 26k 147

(S)-N-(4-(6-(3-(tert- Butyldimethylsilyloxy) pyrrolidine-1-carbonyl)thieno[3,2- d]pyrimidin-4- yloxy)-3-fluorophenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (400 MHz, CDCl₃) δ(ppm): 12.5(s, 1H), 8.79(s, 1H), 8.66(d, 1H, J = 0.4Hz), 8.03-7.91(m,2H), 7.52-7.21(m, 6H), 4.60-4.52(m, 1H), 4.07-3.67(m, 4H), 2.13-1.97(m,2H), 1.28-1.26(m, 2H), 0.93-0.89(m, 9H), 0.14-0.09(m, 6H). 26l 148

tert-Butyl 1-(4-(2- fluoro-4-(3-(2- phenylacetyl)thioureido)phenoxy)thieno[3,2-d] pyrimidine-6- carbonyl)pyrrolidin- 3-ylcarbamate1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.77(s, 1H), 8.09(s, 0.5H), 8.05(s,0.5H), 7.96-7.93(m, 0.5H), 7.93-7.90(m, 0.5H), 7.58-7.50(m, 1H),7.50-7.46(m, 1H), 7.38-7.31(nm, 4H), 7.31-7.24(m, 1H), 3.82(s, 2H),4.15-1.20(m, 7H).

Example 149N-(4-(6-(3-Aminopyrrolidine-1-carbonyl)thieno[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamidehydrochloride(191)

Following the procedure described above for the synthesis of compound159 (scheme 30, example 121) but substituting Boc-protected aminocompound 158 for the Boc-protected amino compound 261, title compound191 was obtained in 40% yield. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):8.77(s, 1H), 8.12(s, 0.5H), 8.06(s, 0.5H), 7.92(dd, J=2.4 and 12.0 Hz,1H), 7.54(t, J=8.4 Hz, 1H), 7.48(dd, J=2.4 and 8.4 Hz, 1H), 7.36-7.31(m,4H), 7.30-7.25(m, 1H), 4.2-3.80(m, 1H), 3.08(s, 2H), 3.80-3.50(m, 4H),2.10-1.98(m, 1H), 1.82-1.64(m, 1H). LRMS (M+1) 550.6 (100%).

Example 1502-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(192a)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with2-(2,6-dichlorophenyl)acetyl isothiocyanate, title compound 192a wasobtained in 7% yield. Characterization of 192a is provided in table 18.

Example 151N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(thiophen-2-yl)acetamide(192b)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with 2-(thiophen-2-yl)acetylisothiocyanate, title compound 192b was obtained in 9% yield.Characterization of 192b is provided in table 18.

Example 1522-(2,6-Difluorophenyl)-N-(3-fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(192c)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with2-(2,6-difluorophenyl)acetyl isothiocyanate, title compound 192c wasobtained in 23% yield. Characterization of 192c is provided in table 18.

Example 153N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)1-phenylcyclopropanecarboxamide (192d)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with1-phenylcyclopropanecarbonyl isothiocyanate, title compound 192d wasobtained in 41% yield. Characterization of 192d is provided in table 18.

Example 154N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylpropanamide(192e)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with 3-methyl-2-phenylbutanoylisothiocyanate, title compound 192e was obtained in 49% yield.Characterization of 192e is provided in table 18.

Example 155N-(3-Fluoro-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-3-phenylpropanamide(192f)

Starting from the amine 169 (scheme 33), following the proceduresdescribed above for the synthesis of compound 170a (example 133) butreplacing 2-phenylacetyl isothiocyanate with 3-phenylpropanoylisothiocyanate, title compound 192f was obtained in 59% yield.Characterization of 192f is provided in table 18.

TABLE 18

Characterization of compounds 192a-f (examples 150-155) Cpd Ex R NameCharacterization 192a 150

2-(2,6- Dichlorophenyl)-N- (3-fluoro-4- (thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl) acetamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm):12.27(s, 1H), 12.01(s, 1H), 8.52(d, J = 5.6Hz, 1H), 8.35-8.00(m, J =12.0Hz, 1H), 7.59(d, J = 5.6Hz, 1H), 7.58-7.47(m, 4H), 7.36(t, J =8.0Hz, 1H), 6.64(d, J = 5.6Hz, 1H), 4.21(s, 2H). 192b 151

N-(3-Fluoro-4- (thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl)-2-(thiophen-2- yl)acetamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm): 12.37(s,1H), 11.80(s, 1H), 8.52(d, J = 5.6Hz, 1H), 8.17(d, J = 5.6Hz, 1H),7.98(d, J = 12.4Hz, 1H), 7.60(d, J = 5.6Hz, 1H), 7.54-7.46(m, 2H),7.42(dd, J = 1.6 and 5.2Hz, H), 7.20-6.97(m, 2H), 6.64(d, J = 5.6Hz,1H), 4.07(s, 2H). 192c 152

2-(2,6- Difluorophenyl)-N- (3-fluoro-4- (thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl) acetamide ¹H NMR (400 MHz, DMSO-d₆) δ(ppm):12.28(s, H), 11.93(s, 1H), 8.52(d, J = 5.6Hz, H), 8.17(d, J = 5.6Hz,1H), 8.03-7.98(m, 1H), 7.60(d, J = 5.6Hz, 1H), 7.57-7.48(m, 2H),7.46-7.37(m, 1H), 7.12(t, J = 7.6Hz, 2H), 6.65(d, J = 5.6Hz, 1H),3.96(s, 2H). 192d 153

N-(3-Fluoro-4- (thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl)-1-phenylcyclopropane carboxamide ¹H NMR (DMSO) δ (ppm): 12.31(1H, s),9.26(1H, s), 8.52(1H, d, J = 5.28Hz), 8.17(1H, d, J = 5.28Hz), 7.96(1H,d, J = 11.93Hz), 7.60(1H, d, J = 5.28Hz), 7.52-7.31(7H, m), 6.64(1H, d,J = 5.09Hz), 1.62(2H, brd, J = 1.96Hz), 1.33(2H, brd, J = 2.35Hz). MS(m/z) 464.2(M+H). 192e 154

N-(3-Fluoro-4- (thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl)-2-phenylpropanamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.50(1H, s),11.77(1H, s), 8.52(1H, d, J = 5.28Hz), 8.16(1H, d, J = 5.48Hz), 8.00(1H,d, J=11.74), 7.60(1H, d, J = 5.48Hz), 7.55-7.48(2H, m), 7.41-7.33(5H,m), 6.63(d, J = 5.48Hz), 4.10(1H, q, J = 6.85Hz), 1.44(3H, d, J =6.85Hz). MS (m/z) 452.1(M+H) 192f 155

N-(3-Fluoro-4- (thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl)-3-phenylpropanamide ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.58(2, 1H),11.62(s, 1H), 8.53(1H, d, J = 5.48Hz), 8.17(1H, d, J = 5.28Hz), 8.03(1H,d, J = 11.35Hz), 7.60(1H, d, J = 5.48Hz), 7.53-7.52(2H, br),7.31-7.21(5H, m), 6.66(1H, d, J = 5.28Hz), 2.92-2.87(2H, m),2.83-2.79(2H, m). MS(m/z) 452.1(M+H)

Example 1562-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(195a) Step 1.(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone(193)

Starting from(7-chlorothieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone (139,scheme 26) and following the procedure described above for the synthesisof compound 6 (scheme 1, example 1), title compound 193 was obtained in(93% yield). LRMS (M+1) 387.4 (100%).

Step 2.(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone(194)

Starting from the nitro compound 183 and following the proceduresdescribed above for the synthesis of amine 7, (scheme 1, example 1)title compound 194 was obtained in 92% yield. LRMS (M+1) 357.4 (100%).

Step 3.2-(2,6-Dichlorophenyl)-N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(195a)

Starting from the amine 194 and following the procedure described abovefor the synthesis of compounds 50 (scheme 10), 170a (scheme 33) or192a-f (scheme 39), title compound 195a was obtained in 70% yield.Characterization of 195a is provided in table 19.

Examples 157-181 (compounds 195b-q)

Compounds 195b-q (examples 157-181) were obtained starting from theamine 194, following the procedure described above for the synthesis ofcompound 195a and replacing 2-(2,6-difluorophenyl)acetyl isothiocyanatewith an appropriately substituted homologue. Characterization of 195b-qis provided in the table 19.

TABLE 19

Characterization of compounds 195a–q (examples 156–181) Cpd Ex R NameCharacterization 195a 156

2-(2,6-Dichlorophenyl)- N-(3-fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.29(s, 1H), 12.02(s,1H), 8.63(d, J = 5.6Hz, 1H), 8.08–8.02(m, 1H), 8.04(s, 1H), 7.62(m, 4H),7.36(dd, J = 7.2 and 8.4Hz, 1H), 6.80(d, J = 5.6Hz, 1H), 4.21(s, 2H),3.85(t, J = 6.4Hz, 2H), 3.54(t, J = 6.4Hz, 2H), 1.97(quint, J = 6.4Hz,2H), 1.88(quint, J = 6.4Hz, 2H). 195b 157

2-(2,6-Difluorophenyl)- N-(3-fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.29(s, 1H), 11.94(s,1H), 8.63(d, J = 5.6Hz, 1H), 8.07–8.01(m, 1H), 8.05(s, 1H), 7.60–7.51(m,2H), 7.46–7.37(m, 1H), 7.18–709(m, 2H), 6.80(d, J = 5.6Hz, 1H), 3.97(s,2H), 3.85(t, J = 6.4Hz, 2H), 3.54(t, J = 6.4Hz, 2H), 1.97(quin, J =6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2H). 195c 158

2-Cyclohexyl-N-(3- fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl) acetamide hydrochloride ¹H NMR(400MHz, DMSO-d₆) δ (ppm): 12.67(s, 1H), 11.55(s, 1H), 8.65(d, J =5.6Hz, 1H), 8.12–8.06(m, 1H), 8.06(s, 1H), 7.60–7.53(m, 2H), 6.82(d, J =5.6Hz, 1H), 3.86(t, J = 6.4Hz, 2H), 3.54(t, J = 6.4Hz, 2H), 2.37(d, J =6.8Hz, 2H), 1.97(quin, J = 6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2H),1.71–1.58(m, 6H), 1.30–1.08(m, 3H), 1.07–0.92(m, 2H). 195d 159

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(4-methoxyphenyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.50(s, 1H), 11.77(s,1H), 8.64(d, J = 5.6Hz, 1H), 8.07–8.01(m, 1H), 8.05(s, H), 7.58–7.53(m,2H), 7.28–7.22(m, 2H), 6.94–6.88(m, 2H), 6.81(d, J = 5.6Hz, 1H), 3.85(t,J = 6.4Hz, 2H), 3.73(s, 2H), 3.73(s, 3H), 3.54(t, J = 6.4Hz, 2H),1.97(quin, J = 6.4Hz, 2H0, 1.89(quin, J = 6.4Hz, 2H). 195e 160

2-(3-Chlorophenyl)-N- (3-fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.83(s,1H), 8.65(d, J = 5.6Hz, 1H), 8.07–8.01(m, 1H), 8.05(s, 1H), 7.59–7.52(m,2H), 7.44–7.26(m, 4H), 6.82(d, J = 5.6Hz, 1H), 3.86(s, 2H), 3.85(t, J =6.4Hz, 2H), 3.54(t, J = 6.4Hz, 2H), 1.97(quin, J = 6.4Hz, 2H),1.89(quin, J = 6.4Hz, 2H). 195f 161

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(thiophen-2-yl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.39(s, 1H), 11.82(s,1H), 8.65(d, J = 5.6Hz, 1H), 8.08–8.00(m, 1H), 8.05(s, 1H),7.60–.7.55(m, 2H), 7.46–7.42(m, 1H), 7.04–6.98(m, 2H), 6.83(d, J =5.6Hz, 1H), 4.06(s, 2H), 3.85(t, J '6.4Hz, 2H), 3.54(t, J '6.4Hz, 2H),1.98(quin, J = 6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2H). 195g 162

2-(2-Chloro-6- fluorophenyl)-N-(3- fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.30(s, 1H), 11.99(s,1H), 8.63(d, J = 5.6Hz, 1H), 8.08–8.01(m, 1H), 8.05(s, 1H), 7.60–7.51(m,2H), 7.44–7.36(m, 2H), 7.30–7.24(m, 1H), 6.80(d, J = 5.6Hz, 1H), 4.07(s,2H), 3.85(t, J = 6.4Hz, 2H), 3.54(t, J = 6.4Hz, 2H), 1.95(quin, J =6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2H). 195h 163

1-(2-Adamantan-1-yl- acetyl)-3-{3-fluoro-4- [2-(pyrrolidine-1-carbonyl)-thieno[3,2- b]pyridin-7-yloxy]- phenyl}-thiourea ¹H NMR(400MHz, DMSO-d₆) δ (ppm): 12.75(s, 1H), 11.45(s, 1H), 8.67(d, J =5.6Hz, 1H), 8.12(d, J = 12.4Hz, 1H), 8.06(s, 1H), 7.62–7.53(m, 2H),6.86(d, J = 5.6Hz, 1H), 3.85(t, J = 6.4Hz, 2H), 3.54(t, J = 6.4Hz, 2H),2.26(s, 2H), 2.02–1.92(m, 5H), 1.89(quin, J =6.4Hz, 2H), 1.70–1.57(m,12H). 195i 164

2-Cyclopentyl-N-(3- fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl) acetamide hydrochloride ¹H NMR(400MHz, DMSO-d₆) δ (ppm): 12.66(s, 1H), 11.55(s, 1H), 8.65(d, J =5.6Hz, 1H), 8.10–8.03(m, 2H), 7.59–7.54(m, 2H), 6.82(d, J = 5.6Hz, 1H),3.86(t, J = 6.4Hz, 2H), 3.54(t, J = 6.4Hz, 2H), 2.20(quin, J = 7.6Hz,1H), 1.97(quin, J = 6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2H), 1.83–1.71(m,2H), 1.68–1.47(m, 4H), 1.26–1.12(m, 2H). 195j 165

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(3,4,5-trimethoxyphenyl)acetamide hydrochloride ¹NMR (400MHz, DMSO-d₆) δ (ppm): 12.49(s, 1H),11.76(s, 1H), 8.60(d, J = 5.6Hz, 1H), 8.07–8.01(m, 2H), 7.58–7.54(m,2H), 6.77(d, J = 5.6Hz, 1H), 6.65(s, 2H), 3.86(t, J = 6.4Hz, 2H),3.76(s, 6H), 3.74(s, 2H), 3.63(s, 3H), 3.54(t, J = 6.4Hz, 2H),1.97(quin, J = 6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2). 195k 166

Methyl 4-(2-(3-(3- fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7- yloxy)phenyl)thioureido)- 2-oxoethyl)benzoate hydrochloride¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.41(s, 1H), 11.86(s, 1H), 8.60(d, J= 5.6Hz, 1H), 8.04(s, 1H), 8.04–8.00(m, 1H), 7.93(d, J = 8.0Hz, 2H),7.58–7.50(m, 2H), 7.47(d, J =8.0Hz, 2H), 6.76(d, J '5.6Hz, 1H), 3.94(s,2H), 3.86(t, J '6.4Hz, 2H), 3.84(s, H), 3.54(t, J = 6.4Hz, 2H),1.97(quin, J = 6.4Hz, 2H), 1.89(quin, J = 64Hz, 2H). 195l 167

(R)-2-(2,2-Dimethyl-5- oxo-1,3-dioxolan-4-yl)- N-(3-fluoro-4-(2-(pyrrolidine-1- carbonyl)thieno[3,2- b]pyridin-7- yloxy)phenylcarbamoyl)ethanethioamide hydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.32(s,1H), 11.73(s, 1H), 8.64(d, J = 5.6Hz, 1H), 8.05(s, 1H), 8.04–8.00(m,1H), 7.60–7.54(m, 2H), 6.81(d, J = 5.6Hz, 1H), 4.93(t, J = 4.4Hz, 1H),3.86(t, J = 6.4Hz, 2H), 3.54(t, J =6.4Hz, 2H), 3.16(dd, J = 4.4 and16.8Hz, 1H), 2.99(dd, J = 5.0 and 16.8Hz, 1H), 1.97(quin, J = 6.4Hz,2H), 1.89(quin, J = 6.4Hz, 2H). 195m 168

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(2-fluorophenyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.88(s,1H), 8.67(d, J = 5.6Hz, 1H), 8.08–8.02(m, 1H), 8.06(s, H), 7.60–7.52(m,2H), 7.43–7.30(m, 2H), 7.24–7.16(m, 2H), 6.85(d, J=5.6Hz, 1H), 3.989s,2H), 3.85(t, J=6.4Hz, 2H), 3.54(t, J = 6.4Hz, 2H), 1.97(quin, J = 6.4Hz,2H), 1.89(quin, J = 6.4Hz, 2H). 195n 169

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(tetrahydro-2H-pyran-4-yl)acetamide hydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm):12.63(s, 1H), 11.59(s, 1H), 8.66(d, J = 5.2Hz, 1H), 8.11–8.02(m, 1H),8.06(s, 1H), 7.60–7.54(m, 2H), 6.84(d, J = 5.2Hz, 1H), 3.85(t, J =6.8Hz, 2H), 3.85–3.79(m, 2H), 3.54(t, J = 6.8Hz, 2H), 3.30(t, J =12.0Hz, 2H), 2.43(d, J = 6.8Hz, 2H), 2.20–1.95(m, 1H), 1.97(quin, J =6.8Hz, 2H), 1.89(quin, J = 6.8Hz, 2H), 1.61(d, J = 12.8Hz, 2H), 1.25(qd,J = 4.0 and 12.0Hz, 2H). 195o 179

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(2-methoxyphenyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.55(s, 1H), 11.73(s,1H), 8.63(d, J = 5.6Hz, 1H), 8.10–8.04(m, 2H), 7.60–7.51(m, 2H),7.26(td, J = 1.6 and 8.0Hz, 1H), 7.21(dd, J =1.6 and 7.6Hz, 1H), 6.99(d,J '8.0Hz, H), 6.90(ts, J '1.2 and 7.6Hz, 1H), 6.80(d, J '5.6Hz, 1H),3.86(t, J = 6.4Hz, 2H), 3.81(s, 2H), 3.78(s, 3H), 3.54(t, J = 6.4Hz,2H), 1.97(quin, J = 6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2H). 195p 180

2-(2,5-Dimethoxyphenyl)- N-(3-fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.53(s, 1H), 11.71(s,1H), 6.64(d, J = 5.6Hz, 1H)< 8.10–8.04(m, 1H), 8.05(s, 1H), 7.60–7.52(m,2H), 6.93–6.78(m, 4H), 3.85(t, J = 6.4Hz, 2H), 3.78(s, 2H), 3.72(s, 3H),3.69(s, 3H), 3.54(t, J = 6.4Hz, 2H), 1.97(quin, J = 6.4Hz, 2H),1.89(quin, J = 6.4Hz, 2H). 195q 181

2-(3,4- Dimethoxyphenyl)-N- (3-fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.51(s, 1H), 11.76(s,1H), 8.69(d, J = 5.6Hz, 1H), 8.08–8.02(m, 1H), 8.07(s, 1H), 7.61–7.54(m,2H), 6.98–6.82(m, 4H), 3.85(t, J = 6.4Hz, 2H), 3.78–3.70(m, 8H), 3.54(t,J = 6.4Hz, 2H), 1.97(quin, J = 6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2H).

Example 182N-(3-Fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-hydroxyphenyl)acetamidehydrochloride (196a)

Starting from the compound 195o and following the procedure describedabove for the synthesis of compound 155k (scheme 29, example 119), titlecompound 196a was obtained in 62% yield. Characterization of 196a isprovided in table 20.

Example 1832-(2,5-Dihydroxyphenyl)-N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamidehydrochloride (196b)

Starting from the compound 195p and following the procedure describedabove for the synthesis of 196a, title compound 196b was obtained in 83%yield. Characterization of 196b is provided in table 20.

Example 1842-(3,4-Dihydroxyphenyl)-N-(3-fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(196c)

Starting from the compound 195q and following the procedure describedabove for the synthesis of 196a, title compound 196c was obtained in 25%yield. Characterization of 196c is provided in table 20.

TABLE 20 Characterization of compounds 196a–c (examples 182–184) Cpd ExR Name Characterization 196a 182

N-(3-Fluoro-4-(2- (pyrrolidine-1- carbonyl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(2-hydroxyphenyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.60(s, 1H), 11.67(s,1H), 9.63(bs, 1H), 8.63(d, J = 5.6Hz, 1H), 8.09–8.00(m, H), 8.05(s, 1H),7.60–7.50(m, 2H), 7.13(d, J = 7.6Hz, 1H), 7.08(t, J = 7.6Hz, 1H),6.83–6.77(m, 2H), 6.74(t, J = 7.6Hz, 1H), 3.85(t, J = 6.4Hz, 2H),3.76(s, 2H), 3.54(t, J = 6.4Hz, 12H), 1.97(quin, J = 6.4Hz, 2H),1.89(quin, J = 6.4Hz, 2H). 196b 183

2-(2,5- Dihydroxyphenyl)-N- (3-fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl) acetamidehydrochloride ¹H NMR (400MHz, DMSO-d₆) δ (ppm): 12.59(s, 1H), 11.59(s,1H), 8.60(d, J = 5.6Hz, 1H), 8.08–8.03(m, 1H), 8.04(s, 1H), 7.58–7.52(m,2H), 6.77(d, J = 5.6Hz, 1H), 6.60(d, J = 8.4Hz, 1H), 6.57(d, J = 2.8Hz,1H), 6.49(dd, J = 2.8 and 8.4Hz, 1H), 3.86(t, J = 6.4Hz, 2H), 3.54(t,j=6.54Hz, 2H), 1.97(quin, J = 6.4Hz, 2H), 1.89(quin, J = 6.4Hz, 2H).196c 184

2-(3,4- Dihydroxyphenyl)-N- (3-fluoro-4-(2- (pyrrolidine-1-carbonyl)thieno[3,2- b]pyridin-7-yloxy) phenylcarbamothioyl) acetamide¹H NMR (400MHz, DMSO-d₆) δ (ppm): 8.53(d, J = 5.6Hz, 1H), 8.07(dd, J =2.4 and 12.0Hz, 1H), 7.94(s, 1H), 7.50–7.44(m, 1H), 7.40(t, J = 8.4Hz,1H), 6.82–6.71(m, 3H), 6.65(dd, J = 2.4 and 8.4Hz, 1H), 3.92(t, J =6.4Hz, 2H), 3.67(t, J = 6.4Hz, 1H), 3.59(s, 2H), 2.09(quin, J = 6.4Hz,2H), 2.02(quin, J = 6.4Hz, 2H).

Example 185N-(4-(2-(4-Hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(200) Step 1. 2-Bromo-7-(4-nitrophenoxy)thieno[3,2-b]pyridine (197)

Starting from the compound 41 (scheme 8) and following the proceduredescribed above for the synthesis of compound 42 (scheme 8) butreplacing 2-fluoro-4-nitrophenol for 4-nitrophenol, title compound 197was obtained in 48% yield. LRMS (M+1) 350.9 (100%). 352.9 (100%).

Step 2. 4-(7-(4-Nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (198)

Starting from the compound 197 and following the procedure describedabove for the synthesis of compound 153 (scheme 28), title compound 198was obtained in 81% yield. LRMS (M+1) 365.0 (100%).

Step 3. 4-(7-(4-Aminophenoxy)thieno[3,2-b]pyridin-2-yl)phenol (199)

Starting from the compound 198 and following the procedure describedabove for the synthesis of compound 154 (scheme 28), title compound 199was obtained in 83% yield. LRMS (M+1) 335.0 (100%).

Step 4.N-(4-(2-(4-Hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(200)

Starting from the compound 199 and following the procedure describedabove for the compound 155a (scheme 28, example 109), title compound 200was obtained in 3% yield. ¹H NMR (400 MHz, DMSO-d₆)

ppm: 12.38 (s, 1H), 11.74 (s, 1H), 9.94 (s, 1H), 8.46 (d, 1H, J=5.3 Hz),7.81 (s, 1H), 7.72 (d, 2H, J=9.0 Hz), 7.69 (dd, 2H, J=6.7/1.8 Hz),7.34-7.27 (m, 7H), 6.86 (dd, 2H, J=6.7/1.8 Hz), 6.61 (d, 1H, J=5.5 Hz),3.82 (s, 2H). LRMS (M+1) 512.1 (100%).

Example 186N-(4-(2-(4-(2-Morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(203) Step 1.4-(2-(4-(7-(4-Nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenoxy)ethyl)morpholine(201)

Starting from the compound 198 (scheme 42) and following the proceduredescribed above for the compound 161 (scheme 31), title compound 201 wasobtained in 69% yield. LRMS (M+1) 478.1 (100%).

Step 2.4-(2-(4-(2-Morpholinoethoxy)phenyl)thieno[3,²-b]pyridin-7-yloxy)benzenamine(202)

Starting from the compound 201 and following the procedure describedabove for the compound 162 (scheme 31), title compound 202 was obtainedin 69% yield. LRMS (M+1) 448.2 (100%).

Step 3.N-(4-(2-(4-(2-Morpholinoethoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(203)

Starting from the compound 202 and following the procedure describedabove for the compound 163a (scheme 31), title compound 203 was obtainedin 30% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.38 (s, 1H), 11.73 (s,1H), 8.47 (d, 1H, J=5.5 Hz), 7.90 (s, 1H), 1H), 7.79 (s, 2H, J=9.0),7.36 (d, 2H, J=9.0 Hz), 7.43-7.27 (m, 7H), 7.05 (d, 2H, J=9.0 Hz), 6.63(d, 1H, J=5.3 Hz), 4.15 (t, 2H, J=5.6 Hz), 3.82 (s, 2H), 3.58 (t, 4H,J=4.6 Hz), 2.71 (t, 2H, J=5.7 Hz), 2.51-2.46 (m, 4H). LRMS (M+1) 625.2(100%).

Example 187N-(3-fluoro-4-(6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(211) Step 1. 4-Chlorothieno[2,3-d]pyrimidine (205)

Starting from thieno[2,3-d]pyrimidin-4(3H)-one (204) [J. Med. Chem.,1999, 42, 26, 5437-5447, Bull. Soc. Chim. Fr., 1975, 587-591] andfollowing the procedure described above for the synthesis of compound 20(scheme 4, example 22), title compound 205 was obtained in 93% yield.LRMS (M+1) 169.1 (100%), 171.1 (32%).

Steps 2-4.(4-Chlorothieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone (208)

Starting from the compound 205 and following the procedures describedabove for the synthesis of amide 5 (scheme 1, steps 2-4, example 1),title compound 208 was obtained [via intermediates 206 and 207], in 76%yield as dark-brown oil (crude material, was used for the next stepwithout additional purification). LRMS (M+1) 268.2 (100%).

Step 5.(4-(2-Fluoro-4-nitrophenoxy)thieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone(209)

Starting from the compound 208 and following the procedures describedabove for the synthesis of nitro compound 6 (scheme 1, step 5, example1), title compound 209 was obtained in 24% yield. LRMS (M+1) 389.1(100%).

Step 6.(4-(4-Amino-2-fluorophenoxy)thieno[2,3-d]pyrimidin-6-yl)(pyrrolidin-1-yl)methanone(210)

Starting from the compound 209 and following the procedures describedabove for the synthesis of amine 7 (scheme 1, step 6, example 1), crudetitle compound 210 was obtained. It was purified by flashchromatography, eluents DCM followed by DCM-MeOH-Et₃N (97.75:2:0.25), toafford title compound 210 in 54% yield as a yellow solid. LRMS (M+1)359.1 (100%).

Step 7.N-(3-Fluoro-4-(6-(pyrrolidine-1-carbonyl)thieno[2,3-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(211)

Starting from the compound 210 and following the procedures describedabove for the synthesis of compound 8a (scheme 1, step 7, example 1),crude title compound 211 was obtained. It was purified by flashchromatography, eluents DCM and DCM-MeOH-Et₃N (97.75:2:0.25) followed bytrituration with a mixture of MeOH-EtOAc, to afford title compound 211in 17% yield as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 12.43(s, 1H), 11.80 (s, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.93 (d, 1H,J=11.7/2.3 Hz), 7.53-7.47 (m, 2H), 7.34-7.26 (m, 5H), 3.90 (t, 2H, J=6.7Hz), 3.83 (s, 2H), 3.55 (t, 2H, J=6.7 Hz), 1.99-1.85 (m, 4H). LRMS (M+1)536.2 (100%).

Example 188 2-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide (170c) Step 1.7-(4-Nitrophenoxy)thieno[3,2-b]pyridine (212)

Staring from the chloride 2, following the procedure described above forthe synthesis of compound 6 (scheme 1, example 1) but substituting2-fluoro-4-nitrophenol for 4-nitrophenol, title compound 212 wasobtained in 89% yield. MS (m/z) 273.0 (M+H).

Step 2. 4-(Thieno[3,2-b]pyridin-7-yloxy)benzenamine (213)

Staring from the nitro compound 212, following the procedure describedabove for the synthesis of amine 49 (scheme 10, example 55), titlecompound 213 was obtained in 90% yield. MS (m/z) 243.1 (M+H).

Step 3.2-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(170c)

Staring from the amine 213, following the procedure described above forthe synthesis of compound 50 (scheme 10, example 55), title compound170c was obtained in 34% yield. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.35(1H, s), 11.69 (1H, s), 8.47 (1H, d, J=5.28 Hz), 8.10 (1H, d, J=5.28Hz), 7.70 (1H, s), 7.68 (1H, s), 7.54 (1H, d, J=5.28 Hz), 7.30-7.22 (7H,m), 6.61 (1H, d, J=5.28 Hz), 3.78 (2H, s). MS (m/z) 420.0 (M+H).

Example 1892-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-yloxy)-2-(trifluoromethyl)phenylcarbamothioyl)acetamide(170d)

Title compound 170d was obtained according to the scheme 45 via athree-step synthesis starting from the chloride 2 and replacing4-nitrophenol [in the first step] with4-nitro-3-(trifluoromethyl)phenol. ¹H NMR (400 MHz, DMSO-d₆) δ (ppm):12.29 (s, 1H), 11.99 (s, 1H), 8.56 (d, J=5.3 Hz, 1H), 8.17 (d, J=5.3 Hz,1H), 7.84 (d, J=8.6 Hz, 1H), 7.74 (d, J=2.7 Hz, 1H), 7.63 (m, 2H), 7.34(m, 4H), 7.26 (m, 2H), 6.75 (d, J=5.3 Hz, 1H), 3.85 (s, 1H). MS (m/z):488.3 (M+H).

Example 1902-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)acetamide(170e)

Title compound 170e was obtained according to the scheme 45 via athree-step synthesis starting from the chloride 2 and replacing4-nitrophenol [in the first step] with 4-nitrobenzenamine.

¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 12.39 (s, 1H), 11.72 (s, 1H), 8.97 (s,1H), 8.35 (d, J=5.1 Hz, 1H), 8.03 (d, J=5.5 Hz, 1H), 7.64 (d, J=8.4 Hz,2H), 7.49 (d, J=5.3 Hz, 1H), 7.38 (m, 4H), 7.32 (d, J=8.4 Hz, 3H), 6.94(d, J=5.5 Hz, 1H), 3.87 (s, 1H). MS (m/z): 419.2 (M+H).

Example 1912-Phenyl-N-(4-(thieno[3,2-b]pyridin-7-ylthio)phenylcarbamothioyl)acetamide(170f)

Title compound 170f was obtained according to the scheme 45 via athree-step synthesis starting from the chloride 2 and replacing4-nitrophenol [in the first step] with 4-nitrobenzenethiol.

¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.65 (1H, s), 11.91 (1H, s), 8.62 (1H,d, J=4.70 Hz), 8.28 (1H, d, J=5.28 Hz), 8.01-7.90 (2H, m), 7.79-7.68(5H, m), 7.23 (1H, m), 3.95 (2H, m). MS (m/z) 436.0 (M+H)

Example 192N-(2-Methoxy-4-(thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(170 g)

Title compound 170 g was obtained according to the scheme 45 via athree-step synthesis starting from the chloride 2 and replacing4-nitrophenol [in the first step] with 3-methoxy-4-nitrophenol [Hodgson,C., J. Chem. Soc., 1929, 2778). ¹H NMR (DMSO) δ (ppm): 12.70 (1H, s),11.71 (1H, s), 8.63 (1H, d, J=8.80 Hz), 8.51 (1H, d, J=5.28 Hz), 8.14(1H, d, J=5.48 Hz), 7.50 (1H, dd, J=5.48, 0.78 Hz), 7.36-7.25 (5H, m),7.13 (1H, d, J=2.54 Hz), 6.89 (1H, dd, J=8.80, 2.54 Hz), 6.69 (1H, d,J=5.48 Hz), 3.82 (5H, s). MS (m/z) 449.55 (M+H).

Example 193N-(2-Methoxy-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(217) Step 1.7-Chloro-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine (214)

Starting from tributyltin compound 98 (scheme 19) and following theprocedure described above for the synthesis of compound 10 (scheme 2,step 2, example 12) but replacing 2-bromothiazole with2-bromo-1-methyl-1H-imidazole, title compound 214 was obtained in 95%yield. MS (m/z) 250.1 (100%), 252.1 (37%), (M+H).

Step 2.7-(3-Methoxy-4-nitrophenoxy)-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine(215)

Starting from compound 214, following the procedure described above forthe synthesis of compound 11 (scheme 2, step 3, example 12) butreplacing 2-fluoro-4-nitrophenol with 3-methoxy-4-nitrophenol [Hodgson,C., J. Chem. Soc., 1929, 2778], title compound 215 was obtained in 9%yield. MS (m/z) 383.1 (M+H).

Step 3.2-Methoxy-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(216)

Starting from compound 215 and following the procedure described abovefor the synthesis of compound 12 (scheme 2, step 4, example 12), titlecompound 216 was obtained in 100% yield. MS (m/z) 353.1 (M+H).

Step 4.N-(2-Methoxy-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(217)

Starting from compound 216 and following the procedure described abovefor the synthesis of compound 13a (scheme 2, step 5, example 12), titlecompound 217 was obtained in 48% yield. ¹H NMR (400 MHz,DMSO-d₆) δ ppm.12.07 (1H, s), 11.59 (1H, s), 8.45 (1H, d, J=5.48 Hz), 7.91 (1H, d,J=8.80 Hz), 7.85 (1H, s), 7.41 (1H, s), 7.24-6.98 (8H, m), 6.66 (1H, d,J=5.67 Hz), 3.99 (3H, s), 3.78 (3H, s), 3.59 (2H, s). MS (m/z) 530.2(M+H).

Example 1942-Cyclohexyl-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220a) Step 1.7-(2-Fluoro-4-nitrophenoxy)-2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridine(218)

Starting from compound 214 (scheme 46) and following the proceduredescribed above for the synthesis of compound 11 (scheme 2, step 3,example 12), title compound 218 was obtained in 45% yield. MS (m/z)371.1 (M+H).

Step 2.3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(219)

Starting from compound 218 and following the procedure described abovefor the synthesis of compound 12 (scheme 2, step 4, example 12), titlecompound 219 was obtained in 86% yield. MS (m/z) 341.1 (M+H).

Step 3:2-Cyclohexyl-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220a)

To a suspension of 219 (50 mg, 0.145 mmol) in THF (1.5 mL) was added2-cyclohexylacetyl isothiocyanate (40 mg, 0.22 mmol) [P. A. S. Smith andR. O. Kan. J. Org. Chem., 1964, 2261] and the reaction mixture wasstirred for 3 hours transferred onto a flash chromatography column andeluted with EtOAc-MeOH mixture (19:1), to afford title compound 220a(27.5 mg, 31% yield) as a light yellow solid. Characterization of 220ais provided in the table 21.

Example 1952-Cyclopentyl-N-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220b)

Title compound 220b was obtained similarly to the compound 220a from theamine 219 and 2-cyclopentylacetyl isothiocyanate [P. A. S. Smith and R.O. Kan. J. Org. Chem. 1964, 2261] in 47% yield. Characterization of 220bis provided in the table 21.

Example 196N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-oxopyrrolidin-1-yl)acetamide(220c)

Title compound 220c was obtained similarly to the compound 220a from theamine 219 and 2-(2-oxopyrrolidin-1-yl)acetyl isothiocyanate [preparedaccording to the reference P. A. S. Smith and R. O. Kan. J. Org. Chem.1964, 2261] in 18% yield. Characterization of 220c is provided in thetable 21.

Example 197N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide(220d)

Title compound 220d was obtained similarly to the compound 220a from theamine 219 and 2-(tetrahydro-2H-pyran-4-yl)acetyl isothiocyanate[prepared according to the reference P. A. S. Smith and R. O. Kan. J.Org. Chem. 1964, 2261] in 15% yield. Characterization of 220d isprovided in the table 21.

Example 198N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamide(220e)

Title compound 220f was obtained similarly to the compound 220a from theamine 219 and acetyl isothiocyanate in 28% yield. Characterization of220f is provided in the table 21.

Example 199 (R)-Methyl4-(3-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)thioureido)-2-hydroxy-4-oxobutanoate(220f)

To a suspension of 219 (60 mg, 0.186 mmol) in THF (1.9 mL) was added(R)-2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetyl isothiocyanate (60mg, 0.28 mmol) [P. A. S. Smith and R. O. Kan. J. Org. Chem. 1964, 2261].The reaction mixture was stirred for 3 hours, concentrated, purified byflash chromatography, eluent EtOAc-MeOH (19:1), to produce a solidmaterial (29.5 mg) which was dissolved in MeOH, treated with HCl (1N inEt₂O, 0.1 mL) and the mixture was stirred for 10 min at roomtemperature. The solution was concentrated, and the residue was purifiedby preparative HPLC (Aquasil C18 column, gradient: 30% MeOH to 95% MeOHin water, 45 min), to afford title compound 220f (15 mg, 13% yield) as awhite solid. Characterization of 220f is provided in the table 21.

TABLE 21

Characterization of compounds 220a–f (examples 194–199) Cpd Ex R NameCharacterization 220a 194

2-Cyclohexyl-N-(3- fluoro-4-(2-(1- methyl-1H-imidazol- 2-yl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl) acetamide ¹HNMR: (DMSO-d₆) δ(ppm): 12.68(s, 1H), 11.57(s, 1H), 8.72(d, 5.5Hz, 1H), 8.40(s, 1H),8.1(m, 1H), 7.88(m, 1H), 7.75(s, 1H), 7.61(m, 2H), 6.90(d, J=5.5Hz, 1H),4.05(s, 3H), 2.37(d, J=6.8Hz, H), 1.79–1.60(m, 6H), 1.28–1.12(m, 3H),1.02–0.94(m, 2H). MS(m/z): 524.3(M+1). 220b 195

2-Cyclopentyl-N-(3- fluoro-4-(2-(1- methyl-1H-imidazol- 2-yl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl) acetamide ¹H NMR (DMSO-d₆) δ(ppm): 12.66(s, 1H), 11.55(s, 1H), 8.5(m, 1H), 8.06(d, J = 12.5Hz, 1H),7.9(s, 1H), 7.55(m, 2H), 7.41(s, 1H), 7.05(s, 1H), 6.69(m, 1H), 4.0(s,3H), 2.5(m, 2H), 2.2(m, 1H), 1.78(m, 2H), 1.61–1.52(m, 4H), 1.18(m, 2H).MS(m/z): 510.2(M+1) 220c 196

N-(3-Fluoro-4-(2-(1- methyl-1H-imidazol- 2-yl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(2-oxopyrrolidin-1-yl)acetamide ¹H NMR (DMSO-d₆) δ (ppm): 8.52(d, J=5.4Hz, 1H), 7.98(m,1H), 7.89(m, 1H), 7.46(m, 2H), 7.40(s, 1H), 7.04(m, 1H), 6.68(d, J =5.3Hz, 1H), 4.18(s, 2H), 3.99(s, 3H), 3.37(m, 2H), 2.27(m, 2H), 2.0(m,2H). MS(m/z): 525.3(M+1). 220d 197

N-(3-Fluoro-4-(2-(1- methyl-1H-imidazol- 2-yl)thieno[3,2-b]pyridin-7-yloxy) phenylcarbamothioyl)- 2-(tetrahydro-2H-pyran-4-yl)acetamide ¹H NMR (DMSO-d₆) δ (ppm): 8.53(d, J = 5.3Hz, 1H),8.03(d, J = 12.5Hz, 1H), 7.89(s, 1H), 7.52(m, 2H), 7.41(m, 1H), 7.04(m,1H), 6.69(d, J = 5.4Hz, 1H), 3.99(s, 3H), 3.82(m, 2H), 3.59(m, 1H),3.3(m, 2H), 2.43(m, 2H), 1.76(m, 2H), 1.25(m, 2H). MS(m/z): 526.2(M+1).220e 198 CH₃ N-(3-Fluoro-4-(2-(1- ¹H NMR (DMSO-d₆) δ (ppm):methyl-1H-imidazol- 12.55(br, 1H), 11.52(br, 1H), 8.53(m, 1H),2-yl)thieno[3,2- 8.03(m, 1H), 7.90(s, 1H), 7.52(m, 2H),b]pyridin-7-yloxy) 7.41(s, 1H), 7.04(s, 1H), 6.69(m, 1H),phenylcarbamothioyl) 4.00(s, 3H), 2.18(s, 2H). acetamide MS(m/z):442.1(M+1). 220f 199

(R)-Methyl 4-(3-(3- fluoro-4-(2-(1- methyl-1H-imidazol- 2-yl)thieno[3,2-b]pyridin-7- yloxy)phenyl)thioureido)- 2-hydroxy-4- oxobutanoate ¹H NMR(DMSO-d₆) δ (ppm): 8.55(d, J=5.5Hz, 1H), 8.04(m, 1H), 7.92(s, 1H),7.55(m, 2H), 7.43(d, J = 1Hz, 1H), 7.06(d, J=1Hz, 1H), 6.70(dd, J=5.5Hz,J=1Hz, 1H), 4.48(dd, J '5.2Hz, J '7.2Hz, 1H), 4.0(s, 3H), 3.67(s, 3H),2.92(dd, J=5.2Hz, J '15.5Hz, 1H), 2.86(dd, J = 7.4Hz, J=15.5Hz, 1H).MS(m/z): 530.2(M+1)

Example 200N-((3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)(methyl)carbamothioyl)-2-phenylacetamide(223) Step 1:N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(13d) andN-(3-fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-phenylacetamide(221)

To a suspension of 219 (400 mg, 1.18 mmol) in THF (12 mL) was added2-2-phenylacetyl isothiocyanate (312 mg, 1.76 mmol) [P. A. S. Smith andR. O. Kan. J. Org. Chem. 1964, 2261], the reaction mixture was stirredfor 3 hours, transferred onto a flash chromatography column and elutedwith EtOAc/MeOH mixture (98:2), to afford title compounds 13d (example15, 254 mg, 42% yield) and 221 (96 mg, 17% yield).

Characterization of 13d (example 15) is provided in the table 2.Compound 221 is characterized by its mass-spectrum: MS (m/z): 459.1(M+1).

Step 2.3-Fluoro-N-methyl-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(222)

To a solution of 221 (274.8 mg, 0.6 mmol) in DMF (6 mL) NaH (60% inmineral oil, 36 mg, 0.9 mmol) was added in one portion at 0° C. and thereaction mixture was stirred for 1 h, followed by addition of MeI (0.037mL, 0.6 mmol). The reaction mixture was allowed to warm up to roomtemperature, stirred overnight, diluted with EtOAc, washed with water,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. Theresidue was treated with 6N HCl (3 mL), and heated at 100° C. for 3 h,cooled to room temperature and partitioned between water and DCM.Aqueous phase was collected, basified with 1N NaOH to pH 11 andextracted with EtOAc. The extract was dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by flash chromatography (eluentEtOAc/MeOH, 9:1) to afford title compound 222 (102 mg, 46% yiled) as asyrup. MS (m/z): 355.1 (M+1).

Step 3:N-((3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)(methyl)carbamothioyl)-2-phenylacetamide(223)

To a suspension of the 222 (102 mg, 2.88 mmol) in THF (3 ml) was added2-phenylacetyl isothiocyanate (51 mg, 0.288 mmol). The reaction mixturewas stirred for 1 hr, transferred onto a chromatography column andeluted with a mixture EtOAc/MeOH (19: 1) to afford title compound 223(30 mg, 20% yield) as a white solid. ¹HNMR: (DMSO-d₆) δ (ppm): 10.88 (s,1H), 8.51 (d, J=5.3 Hz, 1H), 7.91 (s, 1H), 7.41-7.18 (m, 6H), 7.04 (m,4H), 6.5 (d, J=5.3 Hz, 1H), 4.0 (s, 3H), 3.6 (s, 2H), 3.43 (s, 3H). MS(m/z): 532.3 (M+1).

Example 201N-(4-(2-(1-Methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(227) Step 1:7-Chloro-2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridine (224)

Starting from the compound 98 (scheme 19), following the proceduredescribed above for the synthesis of compound 10 (scheme 2, step 2,example 12) but replacing 2-bromothiazole with4-bromo-1-methyl-1H-imidazole, title compound 224 was obtained in 29%yield. MS (m/z): 250.1 (100%), 252.1 (37%) (M+1).

Step 2:2-(1-Methyl-1H-imidazol-4-yl)-7-(4-nitrophenoxy)thieno[3,2-b]pyridine(225)

A mixture of 224 (950 mg, 3.81 mmol), 4-nitrophenol (795 mg, 5.72 mmol),K₂CO₃ (1.05 g, 7.62 mmol) and Ph₂O (5 mL) was stirred at 190° C. for 2 hin a sealed tube, cooled and treated with additional amount of4-nitrophenol (795 mg, 5.72 mmol). The mixture was stirred for anotherhour at the same conditions, cooled to room temperature and diluted withDCM. The DCM solution was extracted with 2N HCl; the aqueous phase wascollected, basified with concentrated ammonium hydroxide solution(pH˜11) and extracted with EtOAc. The extract was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to afford 225 (860 mg,64% yield) as an orange solid. MS (m/z): 353.1(M+1).

Step 3:4-(2-(1-Methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(226)

To a solution of 225 (860 mg, 2.44 mmol) and NiCl₂×6H₂O (1.16 mg, 4.88mmol) in MeOH/THF (49/81 mL) NaBH₄ (278 mg, 7.32 mmol) was carefullyadded. The reaction mixture was stirred for 10 min, concentrated underreduced pressure and the residue was suspended in 10% HCl. Thesuspension was basified with concentrated NH₄OH solution (pH˜11) andextracted with EtOAc.

The extract was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to produce a solid material. The aqueous phase (asuspension) was filtered; the precipitate was collected, washed withMeOH and dried under reduced pressure.

Both precipitate and the solid obtained from the organic phase, werecombined to afford title compound 226 (947.4 mg, crude) as a brown solidthat was used in the next step without further purification. MS (m/z):323.1 (M+1).

Step 4:N-(4-(2-(1-Methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(227)

To a suspension of the 226 (385 mg, ˜0.99 mmol) in THF (10 mL) was added2-phenylacetyl isothiocyanate (263 mg, 1.49 mmol). The reaction mixturewas stirred for 1 hr, transferred onto a chromatography column andeluted with EtOAc/MeOH (9:1) producing a solid material which wasre-crystallized from MeCN to afford title compound 227 (74.3 mg, 15%yield) as a white solid. ¹HNMR: (DMSO-d₆) d(ppm): 12.39 (s, 1H), 11.73(s, 1H), 8.43 (d, J=5.3 Hz, 1H), 7.84 (s, 1H), 7.72 (m, 3H), 7.66 (s,1H), 7.34-7.27 (m, 7H), 6.69 (d, J=5.3 Hz, 1H), 3.82 (s, 2H), 3.72 (s,3H). MS (m/z): 500.1 (M+1).

Example 202N-(4-(2-(1-Methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(228)

Title compound 228 was obtained starting from the compound 214 (scheme46) and following the procedures described above for the synthesis ofcompound 227 (scheme 49, example 201). ¹H NMR (DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.77 (s, 1H), 8.74 (m, 1H), 8.37 (m, 1H), 7.87-7.78 (m, 1H),7.70 (m, 1H), 7.42-7.20 (m, 7H), 6.90 (m, 1H), 4.05 (d, J=1 Hz, 3H),3.83 (s, 2H). MS (m/z): 500.3.

Example 2031-(4-(2-(Methylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thioure(232a) Step 1: 7-Chloro-2-(methylthio)thieno[3,2-b]pyridine (229)

To a solution of 2 (200 mg, 1.18 mmol) in dry THF (11 ml) at −78° C. wasadded n-BuLi (0.57 mL, 2.5M solution on hexane, 1.41 mmol) and theresultant brown precipitate was stirred for 10 minutes. Methyl disulfide(0.16 ml, 1.77 mmol) was added slowly, the mixture was stirred at −78°C. for 3 hours and partitioned between DCM and water. Organic phase wasseparated, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford title compound 229 (0.240 g, 94% yield,crude) as a yellow solid. MS (m/z): 216.1 (100%), 218.1 (39%) (M+1).

Step 2: 7-(2-Fluoro-4-nitrophenoxy)-2-(methylthio)thieno[3,2-b]pyridine(230)

To a suspension of 229 (100 mg, 0.463 mmol) in diphenyl ether (4 mL),was added 2-fluoro-4-nitrophenol (109 mg, 0.695 mmol) and sodiumcarbonate (147 mg, 1.39 mmol). The reaction mixture was heated atr 200°C. overnight, cooled to room temperature, loaded onto a flashchromatography column and eluted with EtOAc/hexane (1:1) to afford titlecompound 230 (0.135 mg, 86% yield) as a yellow solid. MS (m/z): 337.0(M+1).

Step 3:4-(2-(Methylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (231)

To as solution of 230 (84 mg, 0.250 mmol) in acetic acid (5 mL) at 100°C., was added iron powder (0.069 g, 1.249 mmol). The reaction mixturewas allowed to stir for 5 minutes, filtered through a celite pad andconcentrated under reduced pressure. The residue was purified by columnchromatography, eluent DCM/MeOH (50:1), to afford title compound 231 (61mg, 80% yield) as yellow oil. MS (m/z): 307.1 (M+1).

Step4:1-(4-(2-(Methylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232a)

To a suspension of 231 (61 mg) in THF (2 mL) was added 2-phenylacetylisothiocyanate (42 mg, 0,199 mmol). The reaction mixture was stirred for3 hours, concentrated under reduced pressure and the residue waspurified by column chromatography, eluent EtOAc/hexane (35:65), toproduce yellow oil. Purification of this material by preparative HPLC(column C-18 Aquasil, gradient: 60% MeOH to 95% MeOH) afforded titlecompound 232a (25 mg, 26% yield) as a cream solid. Characterization of232a is provided in the table 22.

Example 2041-(4-(2-(Butylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232b)

Starting from the compound 2, following procedures described above forthe synthesis of compound 232a (example 203, scheme 50) but replacingmethyl disulfide with n-butyl disulfide in the step 1, title compound232b was synthesized. Characterization of 232b is provided in the table22.

Example 2051-(4-(2-(Benzylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232c)

Starting from the compound 2, following procedures described above forthe synthesis of compound 232a (example 203, scheme 50) but replacingmethyl disulfide with benzyl disulfide in the step 1, title compound232c was synthesized. Characterization of 232c is provided in the table22.

Example 2061-(4-(2-(Pyridin-2-ylthio)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(232d)

Starting from the compound 2, following procedures described above forthe synthesis of compound 232a (example 203, scheme 50) but replacingmethyl disulfide with 2-pyridyl disulfide in the step 1, title compound232d was synthesized. Characterization of 232d is provided in the table22.

TABLE 22

Characterization of compounds 232a–d (examples 203–206) Cpd Ex R NameCharacterization 232a 203 Me 1-(4-(2-(Methylthio) ¹HNMR: (DMSO-d6) δthieno[3,2-b] (ppm): 12.46(s, 1H), 11.81(s, 1H), pyridin-7-yloxy)-3-8.45(s, 1H), 7.99(d, J = 12.5, 1H), fluorophenyl)-3- 7.51(s, 1H),7.50(s, 1H), 7.46(s, 1H), (2-phenylacetyl) 7.34–7.30(m, 2H),7.30–7.27(m, 3H), thiourea 6.61(d, J = 5.5Hz, 1H), 3.82(s, 2H), 2.71(s,3H). MS(m/z): 484.1. 232b 204 n-Bu 1-(4-(2-(Butylthio) ¹H NMR (DMSO-d₆)δ (ppm): thieno[3,2-b] 12.46(s, 1H), 11.81(s, 1H), 8.46(d, J = 5.5Hz,pyridin-7-yloxy)-3- 1H), 7.98(d, J = 12.44Hz, 1H), 7.54(s, 1H),fluorophenyl)-3-(2- 7.53–7.47(m, 2H), 7.35–7.31(m, 4H),phenylacetyl)thiourea 7.31–7.24(m, 1H), 6.60(d, J = 5.5Hz, 1H), 3.82(s,2H), 3.13(t, J = 7.24Hz, 2H), 1.64(q, J = 7.43Hz, 2H), 1.42(sextuplet, J= 7.43Hz, 2H), 0.90(t, J = 7.24Hz, 3H). MS(m/z): 526.2 232c 205

1-(4-(2-(Benzylthio) thieno[3,2-b]pyridin- 7-yloxy)-3-fluorophenyl)-3-(2- phenylacetyl)thiourea ¹H NMR (DMSO-d₆) δ (ppm):12.46(s, 1H), 11.81(s, 1H), 8.44(d, J=5.5Hz, 1H), 7.98(d, J = 11.83Hz,1H), 7.52–7.45(m, 3H), 7.38–7.22(m, 10H), 6.60(d, J=5.5Hz, 1H), 4.39(s,2H), 3.82(s, 2H). MS(m/z): 560.2 232d 206

1-(4-(2-(Pyridin-2- ylthio)thieno[3,2- b]pyridin-7-yloxy)-3-fluorophenyl)-3- (2-phenylacetyl) thiourea ¹H NMR (DMSO-d6) δ (ppm):8.55(d, J = 5.3Hz, 1H), 8.45(d, J=3.91Hz, 1H), 8.00–7.95(m, 2H),7.74(td, J=7.83Hz; 1.76Hz, 1H), 7.50(s, 2H), 7.35–7.23(m, 8H), 6.70(d,J=5.3Hz, 1H), 3.82(s, 2H), 1.23(s, 1H). MS(m/z): 547.2

Example 2071-(4-(2-(Methylsulfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(207) Step 1:7-(2-Fluoro-4-nitrophenoxy)-2-(methylsulfinyl)thieno[3,2-b]pyridine(233)

To a solution of 230 (400 mg, 1.189 mmol, scheme 50) in DCM (12 mL) at0° C. was added m-CPBA (77%, 272 mg, 1.189 mmol). The reaction mixturewas stirred at 0° C. for 30 minutes, water was added and the phases wereseparated. The organic phase was collected, washed with a 1% sodiumhydroxide solution, dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was purified by column chromatography,eluent DCM/MeOH (20:1), to afford title compound 233 (414 mg, 90% yield,crude), which was used in the next step without further purification. MS(m/z): 353.0 (M+1).

Step 2:4-(2-(Methylsulfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine(234)

To as solution of 233 (400 mg, 1.135 mmol) in acetic acid (10 mL) at100° C., was added iron powder (317 mg, 5.675 mmol). The reactionmixture was stirred for 5 minutes, filtered through a celite pad andconcentrated under reduced pressure. The residue was purified by columnchromatography, eluent EtOAc/hexane (4:1), to afford title compound 234(0.285 g, 69% yield) as a yellow solid. MS (m/z): 323.0 (M+1).

Step 3:1-(4-(2-(Methylsulfinyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(235)

To a suspension of 234 (280 mg, 0.868 mmol) in THF (8 mL) was added2-phenyl acetyl isothiocyanate (185 mg, 1.04 mmol). The reaction mixturewas stirred for 3 hours, concentrated; the solid residue washed withEt₂O and dried, to afford title compound 235 (229 mg, 53% yield) as awhite-rose solid. ¹HNMR: (DMSO-d6) δ (ppm):12.41(s,1H), 11.75(s,1H),8.54(d, J=5.3 Hz, 1H), 7.98 (s, 1H), 7.96(d, J=13.5 Hz, 1H), 7.48(d,J=5.0 Hz, 2H), 7.30-7.26(m, 2H), 7.26-7.18(m, 3H), 6.69(d, J=5.5 Hz,1H), 3.25(s, 2H), 2.98(s, 3H). MS (m/z): 500.1 (M+1).

Example 2081-(4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(238) Step 1:7-(2-Fluoro-4-nitrophenoxy)-2-(methylsulfonyl)thieno[3,2-b]pyridine(236)

To a solution of 233 (50 mg, 0.142 mmol) in DCM (2 mL), was added mCPBA(77%, 33 mg, 0.142 mmol) at 0° C. The mixture was stirred at 0° C. for 1hour, water was added and the phases were separated. The organic layerwas collected, washed with a 1% sodium hydroxide solution, dried overanhydrous Na₂SO₄ and concentrated under reduced pressure to afford titlecompound 236 (46 mg, 88% yield, crude) as a yellow solid which was usedin the next step without additional purification. MS (m/z): 369.0 (M+1).

Step 2:4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine(237)

To a solution of 236 (45 mg, 0.122 mmol) in acetic acid (4 mL) at 100°C., was added iron powder (34 mg, 0.611 mmol). The reaction mixture wasstirred for 5 minutes, filtered through a celite pad and concentratedunder reduced pressure to afford title compound 237 (20 mg, 48% yield,crude) as a yellow oil that was used in the next step without furtherpurification.

MS (m/z): 339.0 (M+1).

Step 3.1-(4-(2-(Methylsulfonyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea(238)

To a suspension of 237 (20 mg, 0.059 mmol) in THF (10 mL) was added2-phenylacetyl isothiocyanate (26 mg, 0.146 mmol). The reaction mixturewas stirred for 2 hours, concentrated under reduced pressure and theresidue was purified by column chromatography, eluent EtOAc/MeOH (19:1),to afford a solid material that was dissolved in a minimum MeOH andprecipitated with hexane to afford title compound 238 (9.6 mg, 31%) as awhite solid.

¹HNMR: (DMSO-d₆) δ (ppm):12.48(s,1H), 11.81(s,1H), 8.69(d,J=5.5 Hz, 1H),8.36(s,1H), 8.03(d, J=12.13 Hz, 1H), 7.55(s,2H), 7.36-7.30(m, 2H),7.30-7.24(m, 3H), 6.86(d,J=5.5 Hz,1H), 3.83(s,2H), 3.54(s,3H). MS (m/z):516.2.

Example 209 N-(3-Fluoro-4-(2-(furan-2-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(242)

Step 1: (7-Chlorothieno[3,2-b]pyridin-2-yl)(furan-2-yl)methanone (239)

To a solution of 2 (100 mg, 0.589 mmol) in THF (6 mL) at −78° C., wasadded n-BuLi (2.5 M in hexane, 0.259 mL, 8,84 mmol) and the reactionmixture was stirred 15 minutes. 2-Furoyl chloride (0.087 mL, 0.884 mmol)was added drop wise; the mixture was stirred for additional 2 hours andpartitioned between DCM and water. The organic layer was separated,dried over anhydrous Na₂SO₄ and concentrated under reduced pressure toafford title compound 239 (35 mg, 23% yield, crude) as a yellow solid,that was used in the next step without additional purification. MS(m/z): 264.0 (100%), 266.0 (40%) (M+1).

Step 2:(7-(2-Fluoro-4-nitrobenzyl)thieno[3,2-b]pyridin-2-yl)(furan-2-yl)methanone(240)

To a suspension of 239 (35 mg, 0.133 mmol) in Ph₂O (2 mL) was added2-fluoro-4-nitrophenol (42 mg, 0.265 mmol) and K₂CO₃ (73 mg, 0.530mmol). The reaction mixture was heated at 180° C. in a sealed flask for60 hrs, cooled down to room temperature, loaded onto a flashchromatography column and eluted with EtOAc/hexane mixture (1:1), toafford title compound 240 (20 mg 39% yield) as a yellow solid. MS (m/z):385.1 (M+1).

Step 3:(7-(4-Amino-2-fluorobenzyl)thieno[3,2-b]pyridin-2-yl)(furan-2-yl)methanone(241)

To as solution of 240 (20 mg, 0.052 mmol) in acetic acid (2 mL) at 100°C., was added iron powder (15 mg, 0.260 mmol). The reaction mixture wasstirred for 3 minutes, filtered through a celite pad and concentratedunder reduced pressure. The residue was purified by flashchromatography, eluent EtOAc/hexane (3:7) to afford title compound 241(3.3 mg, 18% yield) as a yellow solid. MS (m/z): 355.1 (M+1).

Step 4:N-(3-Fluoro-4-(2-(furan-2-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(242)

To a solution of 241 (3.3 mg, 0.0093 mmol) in THF (1 mL) was added2-phenylacetyl isothiocyanate (2 mg, 0.011 mmol). The reaction mixturewas stirred for 3 hours, concentrated under reduced pressure andpurified by column chromatography, eluent EtOAc/hexane (20:80), followedby precipitation from a mixture acetone/hexane. Thus, title compound 242was obtained (2.2 mg, 44% yield) as a yellow solid. ¹HNMR: 1HNMR:(DMSO-d6) δ (ppm):12.49(s, 1H), 11.82(s, 1H), 8.67(d, J=5.5 Hz, 1H),8.63(s, 1H), 8.22(s, 1H), 8.03(d, J=13.1 Hz, 1H), 7.79(d, J=3.7 Hz, 1H),7.60-7.55(m, 2H), 7.55-7.25(m,5H), 6.89-6.87(m, 1H), 6.83(d, J=5.5 Hz,1H), 3.82(s, 2H). MS (m/z): 532.1 (M+1).

Example 210N-(3-Fluoro-4-(5-(methoxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(246) Step 1. 4-(2-Fluoro-4-nitrophenoxy)-5H-pyrrolo[3,2-d]pyrimidine(243)

To a suspension of 27 (0,400 g, 2,60 mmol) [G. B. Evans, R. H. Furneaux,et. al J. Org. Chem., 2001, 66, 17, 5723-57301] in diphenylether (25 ml)was added 2-fluoro-4-nitrophenol (614 mg, 3.90 mmol) and HCl (2N inEt₂O) (0.19 ml, 3.90 mmol). The reaction mixture was heated at 120° C.for 4 hours, cooled to room temperature and concentrated under reducedpressure, to afford title compound 243 (610 mg, 86% yield) as a blacksolid. MS (m/z): 274.1 (M+1).

Step 2:4-(2-Fluoro-4-nitrophenoxy)-5-(methoxymethyl)-5H-pyrrolo[3,2-d]pyrimidine(244)

To a suspension of 243 (150 mg, 0.547 mmol in DMF (6 mL) was added NaH(66 mg, 1.64 mmol). and the reaction mixture was stirred at 0° C. for 1hour. Chloromethyl methyl ester (132 mg, 1.641 mmol) was added drop wiseand the mixture was stirred at room temperature over night. MeOH (2 mL)was added and the mixture was stirred for an additional hour andpartitioned between EtOAc and water. The organic phase was collected,dried over anhydrous sodium sulfate and concentrated under reducedpressure to afford title compound 244 (86 mg, 49% yield, crude) as anorange solid. MS (m/z): 319.1 (M+1).

Step 3:3-Fluoro-4-(5-(methoxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)benzenamine(245)

To as solution of 244 (85 mg, 0.267 mmol) in acetic acid (8 mL) at 100°C., was added iron powder (75 mg, 1.34 mmol). The reaction mixture wasstirred for 5 minutes, filtered through Celite® pad and concentrated todryness; the residue was purified by flash chromatography, eluentDCM/MeOH (30:1) to afford title compound 245 (18 mg, 23% yield) as anorange solid. MS (m/z): 289.1 (M+1).

Step 4:N-(3-Fluoro-4-(5-(methoxymethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(246)

To a suspension of 245 (18 mg, 0.062 mmol) in THF (1 mL) was added2-phenylacetyl isothiocyanate (12 mg, 0.069 mmol). The reaction mixturewas stirred for 3 hours, concentrated under reduced pressure and theresidue was purified by flash chromatography, eluent hexane/EtOAc (3:2)followed by recrystallization (MeCN/water), and preparative HPLC(Aquasil C-18, gradiend: 60% MeOH to 95% MeOH in water), to afford titlecompound 246 (9.2 mg, 33% yield) as a white solid. ¹HNMR: (CD₃OD) δ(ppm): 8.35(s, 1H), 8.03 (d, J=12.4 Hz, 1H), 7.96(d, J=3.13 Hz, 1H),7.44-7.26(m, 6H), 6.69 (d, J=3.13 Hz, 1H), 5.29 (quintuplet, J=6.65 Hz,1H), 3.75(s, 2H), 3.60 (d, J=10.96 Hz, 3H), 1.63(d, J=6.65 Hz, 6H). MS(m/z): 464.16 (M+1).

Example 211N-(3-Fluoro-4-(5-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(249) Step 1: 4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorobenzenamine(247)

A solution of 243 (263 mg, 0.966 mmol, scheme 54) in MeOH (10 mL) andPdCl₂ (1.8 mg, 0.01 mmol) was stirred in the atmosphere of hydrogen for60 hrs. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. Water was added to the residue andthe aqueous solution was extracted with DCM. The extract was dried overanhydrous Na₂SO₄ and concentrated under reduced pressure, to affordtitle compound 247 (170 mg, 72% yield, crude) as a gray solid. MS (m/z):243.08 (M+1).

Step 2:3-Fluoro-4-(5-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)benzenamine(248)

To a suspension of 247 (80 mg, 0.327 mmol) in THF (4 mL), was added PPh₃(258 mg, 0.983 mmol), DEAD (0.155 ml, 0.983 mmol) and isopropanol (0.075ml, 0.983 mmol), and the reaction mixture was allowed to stir for 48hours. 3N HCl solution (1.0 mL) was added and the mixture was extractedwith DCM. Aqueous phase was collected, neutralized with NaOH 10% (pH˜11) and extracted with DCM. The organic phase was collected, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue was purified twice by column chromatography: eluentsEtOAc/hexane (3:7) and MeOH/DCM (1:20), to afford title compound 248 (19mg, 31% yield) as yellow solid. MS (m/z): 287.1 (M+1).

Step 3:N-(3-Fluoro-4-(5-isopropyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(249)

To a suspension of 248 (10 mg, 0.035 mmol) in THF (1 mL) was added2-phenylacetyl isothiocyanate (0.007 mL, 0.038 mmol). The reactionmixture was stirred for 3 hours, concentrated under reduced pressure andthe residue was purified by flash chromatography, eluent EtOAc/hexane(1:1) and preparative HPLC (C-18 Aquasyl column, gradient: 60% to 95%MeOH in water, 45 min), to afford title compound 249 (4 mg, 26% yield)as a white solid. ¹HNMR: (CD₃OD) δ (ppm): 8.35(s, 1H), 8.03 (d, J=12.4Hz, 1H), 7.96(d, J=3.13 Hz, 1H), 7.44-7.26(m, 6H), 6.69 (d, J=3.13 Hz, 1H), 5.29 (quintuplet, J=6.65 Hz, 1H), 3.75(s, 2H), 3.60 (d, J=10.96 Hz,3H), 1.63(d, J=6.65 Hz, 6H). MS (m/z): 464.2 (M+1).

Example 212 N-(4-(5H-Pyrrolo [3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-(2,6-dichlorophenyl)acetamide (250) Step1:N-(4-(5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-(2,6-dichlorophenyl)acetamide(250)

To a solution of 247 (200 mg, 0.819 mmol, scheme 55) in THF (8.2 mL)2-(2,6-dichlorophenyl)acetyl isothiocyanate (302 mg, 1.33 mmol) wasadded. The mixture was stirred for 1 h at room temperature, transferredonto a flash chromatography column and eluted with EtOAc/hexane (1:1).The solid material obtained was triturated with diethyl ether, filteredand dried under reduced pressure, to afford title compound 250 (200 mg,0.408, 50% yield) as a light brown solid. ¹HNMR: (DMSO-d₆) δ (ppm) 12.69(s, 1H), 12.26 (s, 1H), 12.04 (s, 1H), 7.94 (m, 2H), 7.53 (m, 4H), 7.39(m, 1H), 6.72 (m, 1H), 4.22 (s, 2H). MS (m/z): 490.1 (100%, 492.1 (77%)(M+1).

Example 213N-(3-Fluoro-4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(255a) Step 1: 4-Chloro-6-(phenylethynyl)pyrimidin-5-amine (251)

Ethynylbenzene (0.092 mL, 0.92 mmol) was added to a solution of4,6-dichloropyrimidin-5-amine (100 mg, 0.61 mmol), Pd(PPh₃)₄ (140 mg,0.12 mmol), CuI (116 mg, 0.61 mmol) and DIPEA (0.5 mL, 3.05 mmol) in DME(6.1 mL). The reaction mixture was stirred in the dark over night atroom temperature, diluted with DCM, washed sequentially with diluteaqueous citric acid and water, dried over anhydrous Na₂SO₄ andconcentrated under reduce pressure. The residue was purified by flashchromatography, eluent EtOAc/hexane (1:3), to afford title compound 251(30.8 mg, 22% yield) as a yellow solid. MS (m/z): 230.1 (100.0%), 232.1(33%) (M+1).

Step 2: 4-Chloro-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine (252)

To a solution of 251 (30.8 mg, 0.134 mmol) in NMP (1.4 mL) a suspensionof KH in mineral oil (35%, 31 mL, 0.268 mmol) was added in one portion.The mixture was stirred at room temperature overnight and partitionedbetween EtOAc and water. The organic phase was collected, dried overanhydrous Na₂SO₄ and concentrated. The residue was purified by flashchromatography, eluent EtOAc/hexane (1:2) to afford title compoundaffording 252 (22.7 mg, 74% yield). MS (m/z): 230.1 (100%) 232.1 (33%)(M+1).

Step 3: 4-(2-Fluoro-4-nitrophenoxy)-6-phenyl-5H-pyrrolo[3,2-d]pyrimidine(253)

A mixture of 252 (47.9 mg, 0.21 mmol), 4-nitrophenol (50 mg, 0.32 mmol),K₂CO₃ (58 mg, 0.42 mmol) and Ph₂O (4 mL) was stirred at 190° C.overnight in a sealed tube. The mixture was cooled down, more4-nitrophenol (50 mg, 0.32 mmol) was added and the mixture was stirredat 190° C. for additional 8 h. It was cooled again, transferred onto achromatography column and eluted sequentially with EtOAc/hexane (1:10)and EtOAc/hexane (1:3), to afford title compound 253 (71.4 mg, 97%yield) as a white foam. MS (m/z): 351.1 (M+1).

Step 4:3-Fluoro-4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)benzenamine(254)

To a solution of 253 (71.4 mg, 0,21 mmol) in acetic acid (2.1 mL) at100° C., was added iron powder (59 mg, 1.05 mmol). The reaction mixturewas stired for 5 minutes, filtered through a Celite® pad andconcentrated under reduced pressure. The residue was purified by columnchromatography, eluent EtOAc/hexane (2:1), to afford title compound 254(27.9 mg, 40% yield). MS (m/z): 321.1 (M+1).

Step 5:N-(3-Fluoro-4-(6-phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(255a)

To a suspension of the 254 (26.8 mg, 0.84 mmol) in THF (1.6 ml) wasadded 2-phenylacetyl isothiocyanate (23 mg, 0.13 mmol). The mixture wasstirred for 1 hr transferred onto a chromatography column and elutedsequentially with EtOAc/MeOH (9:1) and EtOAc/hexane (1:1), to affordtitle compound 255a (30 mg, 72% yield) as a white solid.

¹HNMR: (DMSO-d₆) δ (ppm):12.65 (s, 1H), 12.43 (s, 1H), 11.79 (s, 1H),8.31 (s, 1H), 8.06 (d, J=7.6 Hz, 2H), 7.91 (m, 1H), 7.52 (m, 4H), 7.43(m, 1H), 7.34, (m, 4H), 7.27 (m, 1H), 7.18 (m, 1H), 3.83 (s, 2H). MS(m/z): 498.2 (M+1).

Example 214N-(3-Fluoro-4-(6-(pyridin-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(255b)

Following the procedures described above for the synthesis of compound255a (example 213, scheme 57) but replacing ethynylbenzene in the step 1with 2-ethynylpyridine, title compound 255b was obtained. ¹H NMR(DMSO-d₆) δ (ppm): 12.85 (br, 1H), 12.65 (br, 1H), 11.75 (br, 1H), 8.71(m, 1H), 8.33 (s, 1H), 8.21 (d, J=8 Hz, 1H), 7.96 (m, 1H), 7.89 (m, 1H),7.52-7.42 (m, 3H), 7.34-7.32 (m, 5H), 7.28 (m, 1H), 3.83 (s, 2H). MS(m/z): 499.2 (M+1).

Example 215N-(4-(2-(4-Methyl-1H-pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(258a) Step 1:2-(4-Methyl-1H-pyrazol-1-yl)-7-(4-nitrophenoxy)thieno[3,2-b]pyridine(256)

A mixture of 197 (300 mg, 0.86 mmol, scheme 42), 4-methyl-1H-pyrazole(69 mg, 0.86 mmol), CuI (16.4 mg, 0.086 mmol),trans-N¹,N²-dimethylcyclohexane-1,2-diamine (24.4 mg, 0.172 mmol) [J. C.Antilla, A. Klapars, et. al. JACS, 2002, 124, 11684-1688] and K₂CO₃ (238mg, 1.72 mmol) in toluene (1.7 mL) was stirred at room temperature in anatmosphere of nitrogen nitrogen overnight, diluted with EtOAc (100 mL),filtered through a Celite® pad, and concentrated under reduced pressure.The residue was purified by flash chromatography with gradient elutionwith EtOAc/hexane (1:1) to EtOAc/hexane (2:1) to afford title compound256 (88.8 mg, 37% yield) as a white solid. MS (m/z): 352.06 (M+1).

Step 2:4-(2-(4-Methyl-1H-pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)benzenamine(257)

To a solution of 256 (168.4 mg, 0.478 mmol) and NiCl_(2×6)H₂O (226 mg,0.956 mmol) in MeOH/THF (10/10 mL) NaBH₄ (72 mg, 1.92 mmol) wascarefully added. The reaction mixture was stirred for 10 min,concentrated to dryness and the resultant solid was suspended in 10%HCl. The aqueous solution was basified (pH ˜11) with concentratedaqueous NH₄OH and extracted with EtOAc. The organic extract wascollected, dried over anhydrous Na₂SO₄ and concentrated under reducedpressure, to afford title compound 257 (134.6.mg, 87% yield) as a whitesolid. MS (m/z): 322.09 (M+1).

Step 3:N-(4-(2-(4-Methyl-1H-pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(258a)

To a suspension of the 257 (134.6 mg, 0.418 mmol) in THF (4.2 mL) wasadded 2-phenylacetyl isothiocyanate (111 mg, 0.627 mmol). The reactionmixture was stirred for 1 hr at room temperature, transferred onto achromatography column and eluted wit a gradient of gradientEtOAc/hexane, 1:1 to 2:1, to provide a beige solid which was trituratedwith diethyl ether to afford title compound 258a (31 mg, 15% yield) as awhite solid. Characterization of 258a is provided in the table 23.

Example 216N-(4-(2-(1H-Pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(258b)

Following the procedures described above for the synthesis of compound258a (example 215, scheme 58) but replacing 4-methyl-1H-pyrazole in thestep 1 with 1H-pyrazole, title compound 258b was obtained.Characterization of 258b is provided in the table 23.

Example 217N-(4-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(258c)

Following the procedures described above for the synthesis of compound258a (example 215, scheme 58) but replacing 4-methyl-1H-pyrazole in thestep 1 with 3,5-dimethyl-1H-pyrazole, title compound 258c was obtained.Characterization of 258c is provided in the table 23.

TABLE 23

Characterization of compounds 258a–c (examples 215–217) Cpd Ex R NameCharacterization 258a 215

N-(4-(2-(4-Methyl-1H- pyrazol-1-yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹HNMR: (DMSO-d₆) δ (ppm):12.42(br, 1H), 11.76(br, 1H), 8.5(m, 2H), 7.75(m, 2H), 7.65(s, 2H),7.32(m, 7H), 6.65(m, 1H), 3.83(s, 2H), 2.12(s, 3H). MS(m/z): 500.0(M+1).258b 216

N-(4-(2-(1H-Pyrazol-1- yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (DMSO-d₆) δ (ppm):12.4(s, 1H), 11.73(s, 1H), 8.74(d, J = 2.5Hz, 1H), 8.45(d, J = 5.7Hz,1H), 7.87(s, 1H), 7.81(m, 1H), 7.74(d, J = 8.8Hz, 1H), 7.34–7.31(m, 7H),6.66(m, 2H), 3.82(s, 2H). MS(m/z): 486.1 258c 217

N-(4-(2-(3,5-Dimethyl- 1H-pyrazol-1- yl)thieno[3,2- b]pyridin-7-yloxy)phenylcarbamothioyl)- 2-phenylacetamide ¹H NMR (DMSO-d₆) δ (ppm):12.44(s, 1H), 11.77(s, 1H), 8.6(d, J = 5.8, 1H), 7.78(m, 2H), 7.49(s,1H), 7.38–7.28(m, 7H), 6.80(d, J = 5.8Hz, 2H), 6.27(s, 1H), 3.83(s, 2H),2.59(s, 3H), 2.21(s, 3H). MS(m/z): 514.1

Example 218N-(4-(1H-Pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(262a) Step 1. 7-Chloro-1H-pyrrolo[2,3-c]pyridine (259)

To a solution of 2-chloro-3-nitropyridine (5 g, 31.5 mmol)) in THF (200mL) at −78° C., was added vinylmagnesium bromide (100 mL, 1.0M in THF)The reaction mixture was stirred at −20° C. for 8 hours, quenched withNH₄Cl solution (20%, 150 mL), extracted with EtOAc, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flashchromatography, eluent EtOAc/hexane (1:5), to afford the title compound259 (1.23 g, 26% yield) as a white solid [Z. Zhang, et al., J. Org.Chem., 2002, 67, 2345-23471]. MS (m/z): 153.1 (M+H) (found).

Step 2. 7-(2-Fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-c]pyridine (260)

A mixture of 259 (420mg, 2.76 mmol), 2-fluoro-4-nitrophenol (651 mg,4.14 mmol) and K₂CO₃(1.14 g, 8.28 mmol) in Ph₂O (15 mL) was heated at200° C. for 6 hours, cooled to room temperature and partitioned betweenEtOAc and water. Organic phase was collected, dried and concentrated.The residue was purified by flash column chromatography with gradientelution from hexane to hexane/EtOAc (3:1), to afford the title compound260 (333 mg, 44% yield) as a yellowish solid. MS (m/z): 274.1(M+H)(found).

Step 3. 4-(1H-Pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorobenzenamine (261)

To a solution of 259(250mg, 1.64mmol) in DMF (16 mL) at 0° C., was addedNaH 197 mg, 4.92 mmol), 60% in mineral oil), and the mixture was stirredfor 30 min, followed by addition of MeI (112 μL, 1.80 mmol.) Thereaction mixture was vigorously stirred at room temperature for 2 hbefore acetic acid )1 ml was added. Solvents were removed under reducedpressure, the residue was partitioned between water and EtOAc. Organicphase was collected, dried over anhydrous Na₂SO₄ and concentrated., Theresidue was purified by flash column chromatography, eluent EtOAc/hexane(1:1), to afford the title compound 263 (200 mg, 92% yield) as anoff-white solid, MS (m/z): 167.1 (M+H)(found).

Step 4.N-(4-(1H-Pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(262a)

A mixture of 261 (44 mg, 0.18 mmol) and 2-phenylacetyl isothiocyanate(36 □L, 0.19 mmol) in THF (2 mL) was stirred at room temperature for 2hours, and concentrated. The residue was purified by flash columnchromatography, eluent EtOAc/hexane (1:1), to afford the title compound262a (30 mg, 40%) as an off-white solid. ¹H NMR (DMSO-d₆) δ (ppm):12.41(s, 1H), 12.07(s, 1H), 11.77(s, 1H), 7.84(dd, 1H, J=10.95 Hz,J₂=2.0 Hz), 7.58(t, 1H), J₁=J₂=2.7 Hz), 7.51(d, 1H, J=5.7 Hz),7.43-7.39(m, 2H), 7.37-7.33(m, 4H), 7.31-7.26(m, 2H), 6.55(dd, 1H,J₁=1.76 Hz, J₂=2.9 Hz), 3.84(s, 2H), MS (m/z): 421.1(M+H) (found).

Example 219N-(3-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(262b) Step 1. 7-Chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine (263)

To a solution of 259 (250mg, 1.64 mmol) in DMF (16 mL) at 0° C. wasadded NaH (197 mg, 4.92 mmol, 60% in mineral oil), and the mixture wasstirred for 30 min, followed by addition of Mel (112 □L, 1.80 mmol). Thereaction mixture was stirred at room temperature for 2 h before aceticacid (1 mL) was added. Solvents were removed under reduced pressure, theresidue was partitioned between water and EtOAc. Organic phase wascollected, dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by flash column chromatography, eluent EtOAc/hexane (1:1), toafford the title compound 263 (200 mg, 92% yield) as an off-white solid.MS (m/z): 167.1(M+H) (found).

Step 2. 7-(2-Fluoro-4-nitrophenoxy)-1-methyl-1H-pyrrolo[2,3-c]pyridine(264)

Starting from the compound 263 and following the procedure describedabove for the synthesis of nitro compound 260 (scheme 59, step 2,example 218), title compound 264 was obtained in 91% yield as a yellowsolid. MS (m/z): 288.1(M+H) (found).

Step3.-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)benzenamine(265)

Starting from the compound 264 and following the procedure describedabove for the synthesis of amine 261 (scheme 59, step 3, example 218),title compound 265 was obtained in 89% yield as an off-white solid. MS(m/z): 258.1(M+H) (found).

Step 4.N-(3-Fluoro-4-(1-methyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(262b)

Starting from the compound 265 and following the procedure describedabove for the synthesis of compound 262a (scheme 59, step 4, example218), title compound 262b was obtained in 87% yield as an off-whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 12.40(s, 1H), 11.78(s, 1H), 7.83(dd,1H, J₁=10.95 Hz, J₂=1.9 Hz), 7.56(d, 1H, 2.7 Hz), 7.49(d, 1H, J=5.5 Hz),7.43-7.39(m, 2H), 7.37-7.33(m, 4H), 7.31-7.26(m, 2H), 6.52(d,1H, J₂=2.9Hz), 4.11(s, 3H), 3.84(s, 2H), MS (m/z): 435.1(M+H) (found).

Example 220

N-(4-(1-Benzyl-1H-pyrrolo[2,3-c]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(262c)

Starting from the compound 259 and following the procedures describedabove for the synthesis of compound 262b (scheme 60, step 4, example219) but using benzyl bromide in step 1 instead of methyl iodide, titlecompound 262c was obtained. ¹H NMR (DMSO-d₆) δ (ppm): 12.36 (s, 1H),11.76(s, 1H), 7.78(m, 1H,), 7.58(t, 1H, J₁=J₂=2.7 Hz), 7.50(d, 1H, J=5.7Hz), 7.34(m, 5H), 7.30-7.221(m, 5H), 7.15(dd, 1H, J₁=8.1 Hz, J₂=0.4 Hz),7.10(t, 1H), 6.60(d, 1H, J=2.9 Hz), 5.68(s, 2H), 3.82(s, 2H). MS (m/z):511.2(M+H) (found).

Example 221N-(4-(1H-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide (269a) Step 1. 7-Chloro-1H-pyrrolo[3,2-b]pyridine (266)

To a solution of 2-chloro-3-nitropyridine (2.0 g, 12.6 mmol) [C.Almansa, et al., J. Med. Chem., 2001, 44, 350-3611] in THF (80 mL) at−78° C., was added vinylmagnesium bromide (80 mL, 1.0M in THF), and thereaction mixture was stirred at −20° C. for 8 hours, quenched with NH₄Clsolution (20%, 100 mL), extracted with EtOAc, dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography, eluent EtOAc/Hexane (1:1), to afford the title compound266 (240 mg, 11%) as yellow crystals. MS (m/z): 153.1 (M+H) (found).

Step 2. 7-(2-Fluoro-4-nitrophenoxy)-1H-pyrrolo[3,2-b]pyridine(267)

A mixture of 266 (180 mg, 1.18 mmol), 2-fluoro-4-nitrophenol (558 mg,3.55 mmol) and K₂CO₃(981 mg, 7.10 mmol) in Ph₂O(4 mL) was heated at 170°C. for 8 hours, cooled to room temperature and partitioned between EtOAcand water. Organic phase was collected, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by flash column chromatographywith gradient elution of hexane, to hexane/EtOAc (1:1), to afford thetitle compound 267 (84 mg, 26% yield) as a yellowish solid. MS (m/z):274.1 (M+H) (found).

Step 3. 4-(1H-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (268)

To a solution of 267 (35 mg, 0.13 mmol) in AcOH (1 mL) at 90° C., wasadded iron powder (36 mg, 0.65 mmol). The reaction mixture was stirredvigorously for 10 min, cooled, filtered through a Celite pad andconcentrated. The residue was partitioned between DCM and NaHCO₃saturated solution. Phases were separated; the aqueous phase wasneutralized with AcOH and extracted with DCM. Primary organic phase andthe extract were combined and concentrated to give the title compound268 (31 mg, 99%) as an off-white solid. MS (m/z): 244.1(M+H) (found).

Step 4.N-(4-(1H-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide (269a)

A mixture of 268 (20 mg, 0.08 mmol) and 2-phenylacetyl isothiocyanate(16 μL, 0.08 mmol) in THF (1 mL) was stirred at room temperature for 2hours and concentrated. The residue was purified by flash columnchromatography (eluent EtOAc) followed by preparative HPLC (columnAqusil C18, gradient elution with 60-95% MeOH in water, 45 min) toafford the title compound 269a (13 mg, 40% yield) as an off-white solid.¹H NMR (CD₃OD) δ (ppm): 8.41(s, 1H), 8.16(d. 1H, J=5.6 Hz), 8.02(dd, 1H,J₁=2.3 Hz, J₂=12.2 Hz), 7.62(d, 1H, J=3.3 Hz), 7.44(m, 1H), 7.37-7.33(m,4H) 7.31-7.26(m, 1H), 6.65(d, 1H, J=3.1 Hz), 6.52(d, 1H, J=5.7 Hz),3.76(s, 2H), MS (m/z): 421.1(M+H) (found).

Example 222N-(4-(1H-Pyrrolo[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-(2,6-dichlorophenyl)acetamidedihydrochloride (269b)

Starting from the compound 268 and following the procedure describedabove for the synthesis of compound 269a (example 221) but replacing2-phenylacethyl isothiocyanate with 2-(2,6-dichlorophenyl)acetylisothiocyanate, a white solid was obtained. This material was dissolvedin MeOH and treated with HCl (1 mL, 1.0M in ether). Solvents wereremoved under the reduced pressure and the residue was lyophilized, toafford the title compound 269b (48% yield) as a yellowish solid. ¹H NMR(DMSO-d₆) δ (ppm): 13.29(s, 1H), 12.32(s, 1H), 12.05(s, 1H), 8.52(d,1H,), 8.14(m, 2H), 7.64(m, 2H), 7.51(d, 1H), 7.37(dd, 1H), 6.86(m, 1H),6.81(dd, 1H), 4.22(s, 2H), MS (m/z): 489.1(M+H) (found).

Example 223N-(4-(6-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(274) Step 1. 6-Bromothieno[3,2-b]pyridin-7-ol (270)

To a solution of thieno[3,2-b]pyridin-7-ol (1, 2.55 g, 16.87 mmol) inacetic acid (50 mL) was added bromine(1.7 mL, 32.72 mmol). The mixturewas heated at 110° C. for 1 h, cooled and the resultant precipitate wasseparated by filtration, to afford the title compound 270 (4.47 g,crude) as a dark brown powder, which was used in next step withoutfurther purification. M/S (m/z): 231.9(M+H) (found).

Step 2. 6-Bromo-7-chlorothieno[3,2-b]pyridine (271)

DMF (0.72 mL) was added slowly to a solution of (COCl)₂ in DCE at 0° C.and the mixture was stirred for 30 min, followed by addition of 270(crude from above). The combined mixture was stirred for 10 min at thesame conditions and was heated to reflux for 3 h. After cooling themixture was concentrated and partitioned between DCM and water. Organicphase was collected and dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by flash column chromatography(eluent EtOAc), to afford the title compound 271 (0.66 g, 70% yieldbased on compound 1) as a yellowish solid. MS (m/z): 249.0(M+H) (found).

Step 3. 6-Bromo-7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine (272)

Starting from the compound 271 and following the procedure describedabove for the synthesis of compound 260 (scheme 59, example 218, step2), title compound 272 was obtained in 61% yield as an off-white solid.MS (m/z): 368.9(M+H).

Step 4. 4-(6-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine(273)

Starting from the compound 272 and following the procedure describedabove for the synthesis of compound 261 (scheme 59, example 218, step3), title compound 273 was obtained in 92% yield as a light brown solid.MS (m/z): 340.0(M+H).

Step 5.N-(4-(6-Bromothieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(274)

Starting from the compound 273 and following the procedure describedabove for the synthesis of compound 262a (scheme 59, example 218, step4), title compound 274 was obtained in 99% yield as a white solid. ¹HNMR (DMSO-d₆) δ (ppm):12.44(s, 1H), 11.79(s, 1H), 8.82(s, 1H), 8.03(d,1H), 7.99(dd, 1H), 7.54(d, 1H), 7.41(dd, 1H), 7.32-7.24(m, 6H), 3.80(s,2H). MS (m/z):517.0 (M+H) (found).

Example 2244-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (279) Step 1. Lithium4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate (275)

To a solution of 2,2,6,6-tetramethylpiperidine (92 μL, 0.54 mmol) in THF(4 mL) at −10° C., n-BuLi (338 μL, 1.6M in hexane, 0.54 mmol) was addeddrop wise and the reaction mixture was stirred at −10° C. for 10 min.Compound 33 (60 mg, 0.36 mmol) [G. B. Evans et al. J. Org. Chem., 2001,66, 17, 5723-5730 and shown in the scheme 6] was added drop wisemaintaining the temperature below −70° C. over a period of 15 min. DriedCO₂-gas was bubbled through the reaction mixture and stirred at roomtemperature overnight. The precipitate thus formed was collected byfiltration and dried to afford the title compound 275 (78mg, 100% yield)as a yellow solid. MS (m/z): 209.9 (RCOOH, M−H) (found).

Step 2.4-Chloro-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (276)

A reaction mixture containing carboxylate 275 (78 mg, 0.36 mmo), oxalylchloride (63 uL, 0.72 mmol), and a drop of DMF in DCM was stirred for 2h. Solvents were removed under reduced pressure and the residue wasre-dissolved in DCM (4 mL). To this solution Me₂NH (360 μL, 0.72 mmol,2M in THF) in THF was added and the mixture was stirred at roomtemperature for 4 h. The solvent was removed under reduced pressure andthe residue was purified by flash column chromatography (eluent EtOAc)to afford the title compound 276 (50 mg, 58% yield) as a yellowishsolid. MS (m/z): 239.1(M+H) (found).

Step 3.4-(2-Fluoro-4-nitrophenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(277)

Starting from the compound 276 and following the procedure describedabove for the synthesis of compound 260 (scheme 59, example 218, step 2)title compound 277 was obtained in 77% yield as an off-white solid. MS(m/z): 360.1(M+H) (found).

Step 4.4-(4-Amino-2-fluorophenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(278)

Starting from the compound 277 and following the procedure describedabove for the synthesis of compound 261 (scheme 59, example 218, step 3)title compound 278 was obtained in 72% yield as an off-white solid. MS(m/z): 330.1(M+H) (found).

Step 5.4-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N,N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(279)

Starting from the compound 278 and following the procedure describedabove for the synthesis of compound 262a (scheme 59, example 218, step4) title compound 279 was obtained in 98% yield as an off-white solid.1H NMR (DMSO-d6) δ (ppm): 12.45(s, 1H), 11.81(s, 1H), 8.43(s, 1H),7.89(m, 1H), 7.46(m, 2H), 7.34(m, 4H), 7.28(m, 1H), 6.93(m, 1H), 4.03(s,3H), 3.82(s, 2H), 3.81(s, 3H), 3.14(s, 3H), 3.06(s, 3H). MS (m/z):507.1(M+H)(found).

Example 225N-(3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(283) Step 1. 4-chloro-6-(methylthio)thieno[3,2-d]pyrimidine (280)

To a solution of 20 (shown in the scheme 4) (200 mg, 1.18 mmol) in THF(11 mL) was added n-BuLi (566 μL, 1.42 mmol, 2.5M in THF) very slowly at−78° C. and the mixture was stirred for 15 min at the same conditions. Asolutions of dimethyl disulfide (160 uL, 1.77 mmol) and Mel (110 μL,1.77 mmol) in THF (1 mL) was added drop wise. The reaction mixture wasstirred for 2 h at −78° C., quenched with saturated aqueus NH₄Clsolution, and extracted with DCM. The extract was dried over anhydrousNa₂SO₄ and concentrated to afford the title compound 280 (210 mg, 82%yield) as a yellowish solid. MS (m/z): 217.0(M+H) (found).

Step 2.4-(2-Fluoro-4-nitrophenoxy)-6-(methylthio)thieno[3,2-d]pyrimidine (281)

A mixture of 280 (210 mg, 0.97 mmol), 2-fluoro-4-nitrophenol (278 mg,1.77 mmol) and K₂CO₃ (560 mg, 3.54 mmol) in Ph₂O (10 mL) was heated at130° C. 60 hours, cooled to room temperature and partitioned betweenEtOAc and water. Organic phase was collected, dried over anhydrousNa₂SO₄, filtered, concentrated and purified by flash columnchromatography with a gradient elution (hexane to hexane/EtOAc, 1:1) toafford the title compound 281 (288 mg, 88% yield) as a yellowish solid.MS (m/z): 338.1(M+H) (found).

Step 3.3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)benzenamine(282)

To a solution of 281 (288 mg, 0.94 mmol) in AcOH (25 mL) at 90° C., wasadded iron powder (238 mg, 4.25 mmol), and the reaction mixture wasstirred vigorously at 90° C. for 10 min, cooled, filtered through aCelite pad and concentrated. The residue was purified by flash columnchromatography (eluent EtOAc) to afford the title compound 282 (248 mg,95%) as an off-white solid. MS (m/z): 308.1(M+H) (found).

Step 4.N-(3-Fluoro-4-(6-(methylthio)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(283)

A mixture of 282 (248mg, 0.80 mmol) and 2-phenylacetyl isothiocyanate(214 mg, 1.20 mmol) in THF (8 mL) was stirred for 2 hours, andconcentrated. The residue was purified by flash column chromatography,eluent EtOAc/hexane (3:7), to afford title compound 283 (200 mg, 52%yield) as an off-white solid. ¹H NMR (DMSO-d₆) δ (ppm): 12.42(s, 1H),11.80(s, 1H), 8.63(s, 1H), 7.85(d, 1H), 7.54-7.44 (m, 3H), 7.35 (m, 4H),7.30(m, 1H), 3.81(s, 2H), MS (m/z): 485.1 (M+H) (found).

Example 226N-(3-Fluoro-4-(6-(methylsulfinyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (286) Step 1.4-(2-Fluoro-4-nitrophenoxy)-6-(methylsulfinyl)thieno[3,2-d]pyrimidine(284)

A mixture of 281 (1.1 g, 3.2 mmol) and m-CPBA (77%, 890 mg, 12.8 mmol)in DCM at 0° C. was stirred for 2 hours, diluted with DCM, washed withice water, NaHCO₃ solution and water again; dried and concentrated togive the title compound 284 (1.15 g, quantitative) as a yellowish solid.MS (m/z): 354.0(M+H) (found).

Step 2.4-(2-Fluoro-4-nitrophenoxy)-6-(methylsulfinyl)thieno[3,2-d]pyrimidine(285)

Starting from the compound 284 and following the procedure describedabove for the synthesis of compound 282 (scheme 64, step 3, example225), title compound 285 was obtained in 34% yield as an off-whitesolid. MS (m/z): 324.0 (M+H) (found).

Step 3.N-(3-Fluoro-4-(6-(methylsulfinyl)thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide (286)

Starting from the compound 285 and following the procedure describedabove for the synthesis of compound 283 (scheme 64, step 4, example225), title compound 286 was obtained in 36% yield as an off-whitesolid. ¹H NMR (DMSO-d₆) δ (ppm): 12.45(s, 1H), 11.83(s, 1H), 8.80(s,1H), 8.13(s, 1H), 7.93(dd, 1H, J₁=2.3 Hz, J₂=10.9 Hz), 7.55 (t, 1H,J=8.6 Hz), 7.48 (m, 1H), 7.34-7.31(m, 4H), 7.28-7.25(m, 1H), 3.81(s,2H), 3.08(s, 3H). MS (m/z): 501.0(M+H) (found).

Example 227 Methyl7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylatehydrochloride (288) Step 1. Methyl7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxylate (287)

Starting from the nitro compound 38 (shown in the scheme 7) andfollowing the procedure described above for the synthesis of compound261 (scheme 59, step 3, example 218), title compound 287 was obtained in86% yield as an off-white solid. MS (m/z):319.0 (M+H) (found).

Step 2. Methyl7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxylatehydrochloride (288)

Starting from the amine 287, following the procedure described above forthe synthesis of compound 269b (scheme 561, example 222) and replacing2-(2,6-dichlorophenyl)acetyl isothiocyanate with 2-phenylacetylisothiocyanate, title compound 288 was obtained in 72% yield as ayellowish solid. ¹H NMR (d-DMSO) δ (ppm): 12.51(s, 1H), 11.84(s, 1H),8.64(dd, 1H, J₁=5.1 Hz, J₂=0.4 Hz), 8.24(s, 1H, J=0.4 Hz), 8.02(dd, 1H,J₁=1.8 Hz, J₂=13.4 Hz), 7.56-7.54(m, 2H), 7.36-7.31(m, 1H), 7.28-7.25(m,1H), 6.81 (d, 1H, J=5.5 Hz), 3.91 (s, 3H), 3.81 (s, 2H). MS (m/z):496.3(M+H) (found).

Example 2287-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(pyrrolidin-3-yl)thieno[3,2-b]pyridine-2-carboxamide(291) Step 1. tert-Butyl3-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboxamido)pyrrolidine-1-carboxylate(289)

A solution of 40 (shown in the scheme 7, 600 mg, 1.54 mmol), tert-butyl3-aminopyrrolidine-1-carboxylate (369 mg, 2.0 mmol) in DCM (15 mL) wasstirred overnight at room temperature. The solvent was removed underreduced pressure and the residue was purified by flash columnchromatography, eluents EtOAc and EtOAc/MeOH (10:1), to afford the titlecompound 289 (160mg, 20%) as an off-white solid. MS (m/z): 503.3 (M+H)(found).

Step 2. tert-Butyl3-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxamido)pyrrolidine-1-carboxylate(290)

A mixture of 289 (90 mg, 0.18 mmol) and Pd(OH)₂ in MeOH (2 mL) washydrogenated at 1 atm for 1 h. The catalyst was filtered off and thefiltrate was concentrated to afford the title compound 290 (60 mg, 70%yield) as a yellowish solid. MS (m/z): 473.2 (M+H) (found).

Step 3.7-(2-Fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-(pyrrolidin-3-yl)thieno[3,2-b]pyridine-2-carboxamide(291)

A solution of 290 (40 mg, 0.084 mmol) and 2-phenylacetyl isothiocyanate(22 mg, 0.126 mmol) in THF (2 mL) was stirred for 30 min. The solventwas removed under reduced pressure and the residue was purified by flashcolumn chromatography (eluent EtOAc), to afford a solid material, whichwas dissolved in a mixture of TFA/DCM (0.5 mL/0.5 mL) and stirred atroom temperature for 2 h. Solvents were removed under reduced pressureand the residue was purified by preparative HPLC (Aqusil C18, gradienteluent, 60-95% MeOH in water, 45 min) to afford the title compound 291(8 mg, 80% yield) as an off-white solid. ¹H NMR (d-DMSO) δ (ppm):9.27(d, 1H), 8.57(d, 1H), 8.37(s, 1H), 8.30(s, 1H), 8.01(d, 1H), 7.53(m,2H), 7.33-7.31(m, 4H), 7.29-7.25(m, 1H), 6.74(d, 1H), 4.46(m, 1H),3.82(s, 2H), 3.11-3.03(m, 2H), 2.18-2.09(m, 2H), 1.93-1.89(m, 2H). MS(m/z): 550.2(M+H) (found).

Example 229N-(2-Aminoethyl)-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxamide(294) Step 1. tert-Butyl2-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridine-2-carboxamido)ethylcarbamate(292)

A solution of 40 (shown in the scheme 7, 100 mg, 0.26 mmol),N-Boc-N-methylethylenediamine hydrochloride (50 mg, 0.26 mmol) and Et₃N(36 μL, 0.52 mmol) in DCM (2 mL) was stirred for 4 h at room temperatureand diluted with EtOAc (10 mL). The combined mixture was washed withbrine and phases were separated. The aqueous phase was extracted withEtOAc, and the extract was combined with the organic phase, dried overanhydrous Na₂SO₄ and concentrated to afford title compound 292 (119 mg,96%, crude) as yellowish solid. MS (m/z): 477.1 (M+H) (found).

Step 2. tert-Butyl2-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridine-2-carboxamido)ethylcarbamate(293)

To a solution of 292 (80mg, 0.17 mmol) in MeOH/THF (1.7 mL/1.7 mL) at 0°C., was added NiCl_(2×6)H₂O (85 mg, 0.35 mmol), followed by addition ofNaBH₄ (26 mg, 0.68 mmol), portion wise. The reaction mixture was stirredfor 15 min, treated with 2N aqueous HCl (2 mL), filtered; the filtratewas neutralized with aqueous NH₄OH to pH 7 and partitioned between EtOAcand water. Organic phase was collected, dried over anhydrous Na₂SO₄ andconcentrated. The residue (75 mg, quantitative yield, crude) was useddirectly in next step without further purification. MS (m/z): 447.1(M+H)(found).

Step 3.N-(2-Aminoethyl)-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)thieno[3,2-b]pyridine-2-carboxamide(294)

Following the procedure described above for the synthesis of compound291 (example 228), title compound was obtained in 3% yield as anoff-white solid. ¹H NMR (d-DMSO) δ (ppm): 9.00(d, 1H), 8.50(m, 1H),8.30(m, 1H), 8.20(d, 1H), 7.92(d, 1H), 7.44(m, 2H), 7.26-7.25(m, 3H),7.21-7.18(m, 1H), 6.66(d, 1H), 3.75(s, 2H), 3.30-3.20(m, 6H). MS (m/z):524.3(M+H).

Example 230N-(3-Fluoro-4-(2-(3-hydroxyazetidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(300) Step 1. tert-Butyl3-(tert-butyldimethylsilyloxy)azetidine-1-carboxylate (295)

A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (1 g, 5.77mmol), TBSCl (6.35 mmol, 956 mg) in DCM (11.5 mL), was stirred for 72hrs at room temperature. The solvent was removed under reduced pressure,EtOAc was added to the residue, and the solid material was removed byfiltration. The filtrate was concentrated under reduced pressure and theresidue was purified by flash chromatography with gradient elution witEtOAc/hexane (9:1) to EtOAc/hexane (1:1), to afford title compound 295(1.25 g, 75% yield) as a syrup. MS (m/z): 310.1 (M+23).

Step 2: 3-(tert-Butyldimethylsilyloxy)azetidine (296)

A mixture of 295 (200 mg, 0.696 mol), DCM (1 mL) and TFA (1 mL) wasstirred for 1 h at room temperature, concentrated under reducedpressure; NaOH (1 M, 15 mL) was added to the residue and the suspensionwas extracted with DCM, the extract was dried (anhydrous Na₂SO₄) andconcentrated, to afford title compound 296 (90.4 mg, 69% yield) as asyrup. MS (m/z): 188.1 (M+1).

Step 3:(3-(tert-Butyldimethylsilyloxy)azetidin-1-yl)(7-chlorothieno[3,2-b]pyridin-2-yl)methanone(297)

Starting from the acyl chloride 4 (scheme 1), replacing dimethyl aminewith the amine 296 and following the procedure described for thesynthesis of amide 5 (scheme 1 as well), title compound 297 was obtainedin 64% yield as a syrup. MS (m/z): 383.0 (M+1).

Step 4:(7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone(298)

Starting from the amide 297 and following the procedure described abovefor the synthesis of compound 230 (scheme 50, example 203), titlecompound 298 was obtained in 39% yield as a syrup. MS (m/z): 389.05(M+1).

Step 5:(7-(4-Amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone(299)

Starting from the nitro compound 298 and following the proceduredescribed above for the synthesis of the amine 231 (scheme 50, example203), title compound 299 was obtained in 83% yield. MS (m/z): 359.07(M+1).

Step 6:N-(3-Fluoro-4-(2-(3-hydroxyazetidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide(300)

Starting from the amine 299, following the procedure described above forthe synthesis of compound 232a (scheme 50, example 203) but replacing2-phenylacetyl isothiocyanate with (2-methoxy-phenyl)-acetylisothiocyanate andtitle compound 300 was obtained in 39% yield as acreamy solid. ¹HNMR: (CD₃OD) δ (ppm): 12.58 (s, 1H), 11.77 (s, 1H), 8.62(m, 1H), 8.09 (d, J=12.3 Hz, 1H), 7.95 (s, 1H), 7.56 (m, 2H), 7.26 (m,2H), 7.00 (m, 1H), 6.92 (m, 1H), 6.77 (m, 1H), 6.50 (d, J=5.9 Hz, 1H),4.81 (m, 1H), 4.59 (m, 1H), 4.35 (m, 2H), 3.87-3.78 (m, 6H). MS (m/z):567.0 (M+1).

Example 231N-(4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)-2-phenylacetamide (302) Step 1.N¹-(2-(1-Methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yl)benzene-1,4-diamine(301)

A mixture of 214 (500 mg, 2.0 mmol, scheme 46) and benzene-1,4-diamine(500 mg, 4.62 mmol) in iso-PrOH (15 mL) was refluxed overnight, cooledto room temperature and filtered. The solid was collected, washed withiso-PrOH/H₂O mixture, to afford the title compound 301 (300 mg, 44%yield) as a yellowish solid. MS (m/z): 322.1(M+H) (found).

Step 2.N-(4-(2-(1-Methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-ylamino)phenylcarbamothioyl)-2-phenylacetamide (302)

Starting from the compound 301, following the procedures described abovefor the synthesis of compound 269b (scheme 61, example 222) butreplacing 2-(2,6-dichlorophenyl)acetyl isothiocyanate with2-phenylacethyl isothiocyanate, title compound 302 was obtained in 12%yield, as a yellow solid. ¹H NMR (d-DMSO) δ (ppm): 12.47(s, 1H),11.76(s, 1H), 10.83(s, 1H), 8.41(d, 1H, J=6.9 Hz), 7.84(s, 1H), 7.80(s,1H), 7.78(s, 1H), 7.55(s, 1H), 7.46(s, 1H), 7.43(s, 1H), 7.32(m, 4H),7.28-7.20(m, 1H), 7.20(s, 1H), 6.94(d, 1H, J=6.8 Hz), 3.98(s, 3H),3.81(s, 2H). MS (m/z): 499.1(M+H) (found).

Example 232N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-fluorophenyl)acetamide di-hydrochloride (303a)

A mixture of aniline 219 (100 mg, 0.29 mmol, scheme 47) and2-(2-fluorophenyl)acetyl isothiocyanate (115 mg, 0.58 mmol) in THF (3mL) was stirred for 1 hour, loaded directly onto a column containingsilica gel and eluted sequentially with EtOAc and EtOAc/MeOH (100:1), toproduce a white solid. This material was suspended in MeOH (5 mL) andHCl (1.0M in ether, 1 mL) was added to form a clear solution that wasevaporated to dryness. The residue was washed with ether, suspended inH₂O, and lyophilized to afford the title compound (80 mg, 45% yield) asa yellowish solid. ¹H-NMR (DMSO-d₆) δ (ppm): 12.42(s, 1H), 11.88(s, 1H),8.65(d. 1H, J=5.5 Hz), 8.20(s, 1H), 8.05(d, 1H, J=1.7 Hz), 7.74(s, 1H),7.58-7.55(m, 3H) 7.39-7.32(m, 2H), 7.21-7.16(m, 2H), 6.82(d, 1H, J=5.5Hz), 4.02(s, 3H), 3.93(s, 2H), MS (m/z): 536.2(M+H) (found).

Example 233N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamidedi-hydrochloride (303b)

Starting from the compound 219, following the procedure described abovefor the synthesis of 303a (example 232) but replacing2-(2-fluorophenyl)acetyl isothiocyanate with 2-(2-methoxyphenyl)acetylisothiocyanate, title compound 303b was obtained in 44% as an off-whitesolid. ¹H NMR (d-DMSO) δ (ppm): 12.55 (s, 1H), 11.73(s, 1H), 8.62(m,1H), 8.09(m, 1H), 7.65(s, 1H), 7.57(m, 1H), 7.43(s, 1H), 7.27-7.20(m,1H), 6.98(d, 1H, J=8.2 Hz), 6.90(dt, 1H, J₁=1.0 Hz, J₂=7.4 Hz), 6.79(m,1H), 4.02(s, 3H), 3.81(s, 2H), 3.77(s, 3H). MS (m/z): 548.3(M+H)(found).

Example 2342-(2-Fluorophenyl)-N-(4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)acetamidedihydrochloride (304)

Starting from the compound 214 (scheme 46) and following the proceduresdescribed above for the synthesis of compound 228 (example 202) and 303a(example 232), title compound 234 was obtained in 31% yield as anoff-white solid. H NMR (d-DMSO) δ (ppm): 12.34(s, 1H), 11.81(s, 1H),8.68(m, 1H,), 8.24(s, 1H), 7.79(m, 3H), 7.62(s, 1H), 7.40-7.13(m, 6H),6.86(d, 1H), 4.02(s, 3H), 3.93(s, 2H). MS (m/z): 518.1(M+H) (found).

SCHEME 71

R Compound No

194 and 305a

219 and 305b

177 and 305c

Examples 235N-(3-Fluoro-4-(2-(pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide hydrochloride (305a)

A mixture of 194 (93 mg, 0.26 mmol, scheme 40) and 2-phenylacetylisocyanate (83 mg, 0.62 mmoL) [J. Hill et al. JACS, 62: 1940; 1595] wasstirred for 1 h at room temperature, loaded directly onto a flashchromatography column and eluted with EtOAc. A white solid was obtained,which was suspended in MeOH and treated with HCl (1 mL, 1.0M in Et₂O) toform a clear solution. The solution was concentrated to form aprecipitate which was collected by filtration, to afford the titlecompound 305a (48 mg, 33% yield) as a white solid. ¹H NMR (d-DMSO) δ(ppm): 11.05(s, 1H), 10.62(s, 1H), 8.57(d, 1H), 8.02(s, 1H), 7.81(d,1H), 7.48-7.43(m, 2H), 7.33-7.25(m, 5H), 6.74(d, 1H), 3.85(t, 2H),3.78(s, 2H), 3.51(t, 2H), 1.98-1.86(m, 2H). MS (m/z): 519.2(M+H)(found).

Example 236N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-2-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide dihydrochloride (305b)

Starting from the compound 219 (scheme 47) and following the proceduredescribed above for the synthesis of compound 305a, title compound 305bwas obtained in 15% yield as a white solid. ¹H NMR (d-DMSO) δ (ppm):11.07(s, 1H), 10.66(s, 1H), 8.67(d, 1H, J=5.5 Hz), 8.27(s, 1H),7.85-7.80(m, 2H), 7.65(s, 1H), 7.51(t, 1H, J=8.6 Hz), 7.46(d, 1H),7.34-7.28(m, 5H), 6.85(d, 1H, J=5.3 Hz), 4.03(s, 3H), 3.74(s, 2H). MS(m/z): 502.2(M+H) (found).

Example 237N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide dihydrochloride (305c)

Starting from the compound 177 (scheme 35) and following the proceduredescribed above for the synthesis of compound 305a, title compound 305cwas obtained in 54% yield as a white solid. ¹H NMR (d-DMSO) δ (ppm):11.08(s, 1H), 10.67(s, 1H), 8.66 (d, 1H, J=6.2 Hz), 8.26(s, 1H), 8.21(s,1H), 7.93(s, 1H), 7.85(dd, 1H, J₁=12.9 Hz, J₂=2.5 Hz), 7.53(t, 1H, J=8.8Hz), 7.65(s, 1H), 7.48-7.45(m, 1H), 7.35-7.30(m, 4H), 7.28-7.24(m, 1H),6.94(d, 1H, J=6.1 Hz), 3.79(s, 3H), 3.75(s, 2H). MS (m/z): 502.1(M+H)(found).

Example 238 N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide (307)3-Fluoro-4-[2-(1-methyl-1H-imidazol-5-yl)-thieno[3,2-b]pyridin-7-yloxy]-phenylamine(306)

Starting from the compound 98 (scheme 19) and following the proceduresdescribed above for the synthesis of compound 12 (scheme 2, steps 1-4)but replacing 2-bromothiazole at the Stille coupling stage with5-bromo-1-methyl-1H-imidazole (Table 9), title compound 306 wasobtained. MS (m/z): 341.0M+H) (found).

N-(3-Fluoro-4-(2-(1-methyl-1H-imidazol-5-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamoyl)-2-phenylacetamide (307)

A mixture of 306 (99mg, 0.29 mmol) and 2-phenylacetyl isocyanate (97 mg,0.60 mmoL) [A. J. Hill, et al. JACS, 62, 1940; 1595] was stirred for 1 hat room temperature, loaded directly onto a flash chromatography columnand gradient eluted with EtOAc, to MeOH/EtOAc (10:90) to afford thetitle compound 307 (42% yield) as a white solid. ¹H NMR (d-DMSO) δ(ppm): 11.11(s, 1H), 10.68(s, 1H, J=5.5 Hz), 8.49(d), 7.85(s, 1H),7.82(dd, 1H, J₁=12.9 Hz, J₂=2.4Hz), 7.76(s, 1H), 7.43(m, 2H), 7.40(s,1H), 7.32(m, 4H), 7.28(m, 1H), 6.61(d, 1H, J=5.5 Hz), 3.89(s, 3H),3.74(s, 2H). MS (m/z):502.4 (M+H) (found).

Example 239N-(4-(2-(1-Ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamoyl)-2-phenylacetamide (309a)4-[2-(1-Ethyl-1H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yloxy]-3-fluoro-phenylamine(308)

Starting from the compound 98 (scheme 19) and following the proceduresdescribed above for the synthesis of compound 12 (scheme 2, steps 1-4)but replacing 2-bromothiazole at the Stille coupling stage with4-bromo-1-ethyl-1H-imidazole (Table 9), title compound 308 was obtained.MS (m/z): 355.1 (M+H) (found).

N-(4-(2-(1-Ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamoyl)-2-phenylacetamide (309a)

A mixture of 308 (300 mg, 0.85 mmol) and 2-phenylacetyl isocyanate (164mg, 1.02 mmoL) [Arthur J. Hill, et al. JACS, 62: 1940; 1595] was stirredfor 1 h at room temperature, loaded directly onto a flash chromatographycolumn and gradient eluted with EtOAc, to MeOH/EtOAc (20:80) to affordthe title compound 309a (45% yield) as a white solid. ¹H NMR (d-DMSO) δ(ppm): 11.07(s, 1H), 10.63(s, 1H), 8.41(d, 1H, J=5.5 Hz), 7.94(d, 1H,J=1.4 Hz), 7.80(dd, 1H, J₁=13.1 Hz, J₂=2.4 Hz), 7.77(d, 1H, J=1.1 Hz),7.65(s, 1H), 7.46-7.39(m, 2H), 7.35-7.19(m, 4H), 7.28-7.24(m, 1H),6.54(dd, 1H, J₁=5.5 Hz, J₂=0.8 Hz), 4.03(q, 2H), 3.73(s, 2H), 1.38(t,3H). MS (m/z): 516.1(M+H) (found).

Example 240N-(4-(2-(1-Ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamoyl)-2-(2-fluorophenyl)acetamide (309b)

A mixture of 308 (320 mg, 0.90 mmol) and (2-fluoro-phenyl)-acetylisocyanate (600 mg, 3.35 mmoL) [A. J. Hill, et al. JACS, 62; 1940; 1595]was stirred for 1 h at room temperature, loaded directly onto a flashchromatography column and gradient eluted with EtOAc, toMeOH/EtOAc(20:80), to afford the title compound 309b in 42% yield as awhite solid. ¹H NMR (d-DMSO) δ (ppm): 11.10(s, 1H), 10.58(s, 1H),8.42(d, 1H, J=5.5 Hz), 7.94(d, 1H, J=1.1 Hz), 7.82-7.77(m, 2H), 7.65(s,1H), 7.45-7.30(m, 4H), 7.19-7.16(m, 2H), 6.54(dd, 1H, J₁=0.7 Hz, J₂=5.4Hz), 4.04(q, 2H), 3.83(s, 2H), 1.38(t, 3H). MS (m/z): 534.1(M+H)(found).

Example 241N-(4-(2-(1-Ethyl-1H-imidazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamoyl)-2-(2-methoxyphenyl)acetamide (309c)

A mixture of 308 (370 mg, 1.05 mmol) and (2-methoxy-phenyl)-acetylisocyanate (240 mg, 1.25 mmoL) [A. J. Hill, et al. JACS, 62; 1940; 1595]was stirred for 1 h at room temperature, loaded directly onto a flashchromatography column and eluted with EtOAc, to afford the titlecompound 309c in 42% yield as a white solid. ¹H NMR (d-DMSO) δ (ppm):10.98(s, 1H), 10.69(s, 1H), 8.41(d, 1H, J=5.3 Hz), 7.94(d, 1H, J=1.2Hz), 7.81(dd, 1H, J₁=13.1 Hz, J₂=2.4 Hz), 7.77(d, 1H, J=0.9 Hz), 7.65(s,1H), 7.45-7.40(m, 2H), 7.26-7.19(m, 2H), 6.97(d, 1H, J=8.0 Hz), 6.89(dt,1H, J₁=0.8 Hz, J₂=8.2 Hz), 6.54(d, 1H, J=5.5 Hz), 4.04(q, 2H), 3.75(s,3H), 3.70(s, 2H), 1.38(t, 3H). MS (m/z): 546.1(M+H) (found).

Example 2421-{4-[2-(1-Ethyl-1H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yloxy]-3-fluoro-phenyl}-3-[2-(2-fluoro-phenyl)-acetyl]-thiourea(310a)

To a suspension of the 308 (385 mg, 0.99 mmol) in THF (10 mL) was added2-(2-fluorophenyl)acetyl isothiocyanate (263 mg, 1.49 mmol) and thereaction mixture was stirred for 1 hr, transferred onto a flashchromatography column and eluted with EtOAc/MeOH 19:1, to afford titlecompound 310a (366.9 mg, 67% yield) as a creamy solid. ¹HNMR: (DMSO-d₆)δ (ppm): 12.42 (s, 1H), 11.87 (s, 1H), 8.44 (d, J=5.5 Hz, 1H), 8.02 (d,J=11.5 Hz, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.67 (s, 1H), 7.52 (m, 2H),7.42 (m, 2H), 7.25 (m, 2H), 7.06 (d, J=5.5 Hz, 1H), 4.04 (q, J=7.3 Hz,2H), 3.92 (s, 2H), 7.4 (t, J=7.3 Hz, 3H). MS (m/z): 550.0 (M+1).

Example 2431-{4-[2-(1-Ethyl-1H-imidazol-4-yl)-thieno[3,2-b]pyridin-7-yloxy]-3-fluoro-phenyl}-3-[2-(2-methoxy-phenyl)acetyl]-thiourea(310b)

Starting from the compound 308, following the procedure described abovefor the synthesis of 310a but replacing 2-(2-fluorophenyl)acetylisothiocyanate with (2-methoxy-phenyl)-acetyl isothiocyanate, titlecompound 310b was obtained in 82% yield. ¹H NMR (DMSO-d₆) δ (ppm): 12,57(s, 1H), 11.76 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.07 (m, 1H), 7.96 (d,J=1 Hz, 1H), 7.79 (d, J=1 Hz, 1H), 7.69 (s, 1H), 7.6 (m, 2H), 7.26 (m,2H), 7.0 (d, J=7.4 Hz, 1H), 6.92 (m, 1H), 6.59 (d, J=5.5 Hz, 1H), 4.06(q, J=7.5 Hz, 2H), 3.82 (s, 2H), 3.79 (s, 3H), 1.4 (t, J=7.4 Hz, 3H). MS(m/z): 562.0 (M+1).

Example 244

N-Ethyl-7-(2-fluoro-4-(3-(2-phenylacetyl)thioureido)phenoxy)-N-methylthieno[3,2-b]pyridine-2-carboxamide(311)

Title compound 311 was obtained by following the procedures describedabove for the synthesis of compound 8a (scheme 1, example 1) butreplacing dimethylamine in the step 4 with N-methylethanamine. ¹H NMR(400 MHz, DMSO-d6) (ppm) 12.49 (s, 1H), 11.82 (s, 1H), 8.64 (d, J=5.48Hz, 1H), 8.03 (d, J=12.7 Hz, 1H) 7.85 (m, 1H), 7.54 (m, 2H), 7.32 (m,4H), 7.24 (m, 1H), 6.82 (d, J=5.3 Hz, 1H), 3.83 (s, 2H), 3.53 (m, 2H),3.38 (m, 2H), 3.05 (s, 1H), 1.10 m, 3H). MS (calcd.) 522.1, found 523.2(M+H).

Example 245

N-(4-(2-(4-(Dimethylamino)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide(312)

Title compound 312 was obtained by following the procedures describedabove for the synthesis of compound 50 (scheme 10, example 55) butreplacing4,4,5,5-tetramethyl-2-(4-(methylsulfonyl)phenyl)-1,3,2-dioxaborolane inthe first step with 4-(dimethylamino)phenylboronic acid. ¹H NMR (DMSO):12.48 (1H, s), 11,83 (1H, s), 8.44 (1H, d, J=5.48 Hz), 7.99 (1H, d,J=12.91 Hz), 7.77 (1H, s), 7.68 (2H, d, J=8.41 Hz), 7.51 (2H, br),7.33-7.28 (5H, m), 6.77 (2H, d, J=8.22 Hz), 6.56 (1H, d, J=4.89 Hz),3.81 (2H, s), 2.96 (6H, s).

MS: calcd: 556.7, found: 556.9 (M+H).

Example 246

N-(3-Fluoro-4-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide(313)

Title compound 313 was obtained by following the procedures describedabove for the synthesis of compound 75 (scheme 15) but starting from4-(3-bromobenzyl)morpholine instead of tert-butyl3-bromobenzyl(2-methoxyethyl)carbamate (65). ¹H NMR (DMSO): 12.49 (1H,s), 11.84 (1H, s), 8.52 (1H, d, J=5.48 Hz), 8.05 (1H, s), 8.01 (1H, d,J=12.72Hz), 7.79-7.78 (2H, m), 7.53 (2H, br), 7.46 (1H, t, J=7.63 Hz),7.39 (1H, d, J=7.63 Hz), 7.34-7.26 (5H, m), 6.66 (1H, d, J=5.28 Hz),3.82 (2H, s), 3.57 (4H, br), 3.32 (2H, s), 2.38 (4H, br). MS: calcd:612.7, found: 613.3 (M+1).

Example 247

N-(3-Fluoro-4-(thieno[3,2-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(314)

Title compound 314 was obtained by following the procedures describedabove for the synthesis of compound 173 (scheme 34, example 135) butreplacing 3-chloro-4-nitrophenol in the step 1 with2-fluoro-4-nitrophenol. ¹HNMR (DMSO-d₆) δ (ppm): 12.42 (bs, 1H), 11.79(bs, 1H), 8.71 (s, 1H), 8.51 (d, J=5.2 Hz, 1H), 7.91 (dd, J=2.4 and 12.0Hz, 1H), 7.70 (d, J=5.2 Hz, 1H), 7.53 (dd, J=8.4 Hz, 1H), 7.47 (dd,J=2.4 and 8.4 Hz, 1H), 7.38-7.30 (m, 4H), 7.30-7.27 (m, 1H), 3.82 (s,2H). LRMS: 438.1(calc) 439.1 (found).

Example 248

N-(3-Fluoro-4-(thieno[2,3-d]pyrimidin-4-yloxy)phenylcarbamothioyl)-2-phenylacetamide(315)

Title compound 315 was obtained starting from the compound 205 (scheme44) and following the procedures described above for the synthesis ofcompound 314. ¹HNMR (DMSO-d₆) δ (ppm): 12.42 (s, 1H), 11.80 (s, 1H),8.63 (s, 1H), 8.01 (d, J=5.6 Hz, 1H), 7.91 (dd, J=2.0 and 12.0 Hz, 1H),7.70 (d, J=5.6 Hz, 1H), 7.50 (t, J=8.4 Hz, 1H), 7.46 (dd, J=2.4 and 8.4Hz, 1H), 7.36-7.30 (m, 4H), 7.30-7.24 (m, 1H), 3.82 (s, 2H). LRMS: 438.4(calc) 439.3 (found).

Example 249

N-(4-(5H-Pyrrolo[3,2-d]pyrimidin-4-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide (316)

Title compound 316 was obtained by following the procedures describedabove for the synthesis of compound 31 a (scheme 5, example 28) butskipping N-methylation step.

¹HNMR (DMSO-d₆) δ (ppm): 12.41(s, 1H), 8.32 (s, 1H), 7.91 (d, J=10 Hz,1H), 7.48 (s, 1H), 7.56-7.42 (m, 2H), 7.39-7.32 (m , 4H), 7.30-7.22 (m,1H), 6.66 (s, 1H), 3.83 (s, 2H). LRMS: 421.1 (calc) 422.1 (found).

Assay Examples Assay Example 1 Inhibition of c-met and VEGF Activity

The following protocols were used to assay the compounds of theinvention.

In Vitro Receptor Tyrosine Kinase Assays (c-Met/HGF Receptor and VEGFReceptor KDR)

These tests measure the ability of compounds to inhibit the enzymaticactivity of recombinant human c-Met/HGF receptor and VEGF receptorenzymatic activity.

A 1.3-kb cDNA corresponding to the intracellular domain of c-Met orc-Met IC (Genbank accession number NP000236-1 amino acid 1078 to 1337)was cloned into the BamHI/XhoI sites of the pBlueBacHis2A vector(Invitrogen) for the production of a histidine-tagged version of thatenzyme. This constuct was used to generate recombinant baculovirus usingthe Bac-N-Blue™ system according to the manucfacturer's instructions(Invitrogen)

The c-Met IC protein was expressed in Hi-5 cells (Trichoplusia Ni) uponinfection with recombinant baculovirus construct. Briefly, Hi-5 cellsgrown in suspension and maintained in serum-free medium (Sf900 IIsupplemented with gentamycin) at a cell density of about 2×10⁶ cells/mlwere infected with the abovementioned viruses at a multiplicity ofinfection (MOI) of 0.2 during 72 hours at 27° C. with agitation at 120rpm on a rotary shaker. Infected cells were harvested by centrifugationat 398 g for 15 min. Cell pellets were frozen at −80° C. untilpurification was performed.

All steps described in cell extraction and purification were performedat 4° C. Frozen Hi-5 cell pellets infected with the C-Met IC recombinantbaculovirus were thawed and gently resuspended in Buffer A (20 mM TrispH 8.0, 10% glycerol, 1 μg/ml pepstatin, 2 μg/ml Aprotinin andleupeptin, 50 μg/ml PMSF, 50 μg/ml TLCK and 10 μM E64, 0.5 mM DTT and 1mM Levamisole) using 3 ml of buffer per gram of cells. The suspensionwas Dounce homogenized after which it was centrifuged at 22500 g, 30min., 4° C. The supernatant (cell extract) was used as starting materialfor purification of c-Met IC.

The supernatant was loaded onto a QsepharoseFF column (AmershamBiosciences) equilibrated with Buffer B (20 mM Tris pH 8.0, 10%glycerol) supplemented with 0.05M NaCl. Following a ten column volume(CV) wash with equilibration buffer, bound proteins were eluted with a 5CV salt linear gradient spanning from 0.05 to 1M NaCl in Buffer B.Typically, the conductivity of selected fractions ranked between 6.5 and37 mS/cm. This Qsepharose eluate had an estimated NaCl concentration of0.33M and was supplemented with a 5M NaCl solution in order to increaseNaCl concentration at 0.5M and also with a 5M Imidazole (pH 8.0)solution to achieve a final imidazole concentration of 15 mM. Thismaterial was loaded onto a HisTrap affinity column (GE Healthcare)equilibrated with Buffer C (50 mM NaPO₄ pH 8.0, 0.5M NaCl, 10% glycerol)supplemented with 15 mM imidazole. After a 10 CV wash with equilibrationbuffer and an 8 CV wash with buffer C +40 mM imidazole, bound proteinswere eluted with an 8 CV linear gradient (15 to 500 mM) of imidazole inbuffer C. C-Met IC enriched fractions from this chromatography step werepooled based on SDS-PAGE analysis. This pool of enzyme underwent bufferexchange using PD-10 column (GE Healthcare) against buffer D (25 mMHEPES pH 7.5, 0.1M NaCl, 10% glycerol and 2 mM □-mercaptoethanol) FinalC-Met IC protein preparations concentrations were about 0.5 mg/ml withpurity approximating 80%. Purified c-Met IC protein stocks weresupplemented with BSA at 1 mg/ml, aliquoted and frozen at −80° C. priorto use in enzymatic assay.

In the case of VEGF receptor KDR a 1.6-kb cDNA corresponding to thecatalytic domain of VEGFR2 or KDR (Genbank accession number AF035121amino acid 806 to 1356) was cloned into the Pst I site of the pDEST20Gateway vector (Invitrogen) for the production of a GST-tagged versionof that enzyme. This constuct was used to generate recombinantbaculovirus using the Bac-to-Bac™ system according to themanucfacturer's instructions (Invitrogen).

The GST-VEGFR2₈₀₆₋₁₃₅₆ protein was expressed in Sf9 cells (Spodopterafrugiperda) upon infection with recombinant baculovirus construct.Briefly, Sf9 cells grown in suspension and maintained in serum-freemedium (Sf900 II supplemented with gentamycin) at a cell density ofabout 2×10⁶ cells/ml were infected with the abovementioned viruses at amultiplicity of infection (MOI) of 0.1 during 72 hours at 27° C. withagitation at 120 rpm on a rotary shaker. Infected cells were harvestedby centrifugation at 398 g for 15 min. Cell pellets were frozen at −80°C. until purification was performed.

All steps described in cell extraction and purification were performedat 4° C. Frozen Sf9 cell pellets infected with the GST-VEGFR2₈₀₆₋₁₃₅₆recombinant baculovirus were thawed and gently resuspended in Buffer A(PBS pH 7.3 supplemented with 1 μg/ml pepstatin, 2 μg/ml Aprotinin andleupeptin, 50 μg/ml PMSF, 50 μg/ml TLCK and 10 μM E64 and 0.5 mM DTT)using 3 ml of buffer per gram of cells. Suspension was Douncehomogenized and 1% Triton X-100 was added to the homogenate after whichit was centrifuged at 22500 g, 30 min., 4° C. The supernatant (cellextract) was used as starting material for purification ofGST-VEGFR2₈₀₆₋₁₃₅₆.

The supernatant was loaded onto a GST-agarose column (Sigma)equilibrated with PBS pH 7.3. Following a four column volume (CV) washwith PBS pH 7.3+1% Triton X-100 and 4 CV wash with buffer B (50 mM TrispH 8.0, 20% glycerol and 100 mM NaCl), bound proteins were step elutedwith 5 CV of buffer B supplemented with 5 mM DTT and 15 mMglutathion.GST-VEGFR2₈₀₆₋₁₃₅₆ enriched fractions from thischromatography step were pooled based on U.V. trace i.e. fractions withhigh O.D.₂₈₀. Final GST-VEGFR2₈₀₆₋₁₃₅₆ protein preparationsconcentrations were about 0.7 mg/ml with purity approximating 70%.Purified GST-VEGFR2₈₀₆₋₁₃₅₆ protein stocks were aliquoted and frozen at−80° C. prior to use in enzymatic assay.

Inhibition of c-Met/HGF receptor and VEGFR/KDR was measured in a DELFIA™assay (Perkin Elmer). The substrate poly(Glu₄,Tyr) was immobilized ontoblack high-binding polystyrene 96-well plates. The coated plates werewashed and stored at 4° C. During the assay, enzymes were pre-incubatedwith inhibitor and Mg-ATP on ice in polypropylene 96-well plates for 4minutes, and then transferred to the coated plates. The subsequentkinase reaction took place at 30° C. for 10-30 minutes. ATPconcentrations in the assay were 10 uM for C-Met (5× the K_(m)) and 0.6uM for VEGFR/KDR (2× the K_(m)). Enzyme concentration was 25 nM (C-Met)or 5 nM (VEGFR/KDR). After incubation, the kinase reactions werequenched with EDTA and the plates were washed. Phosphorylated productwas detected by incubation with Europium-labeled anti-phosphotyrosineMoAb. After washing the plates, bound MoAb was detected by time-resolvedfluorescence in a Gemini SpectraMax reader (Molecular Devices).Compounds were evaluated over a range of concentrations and IC₅₀'s(concentration of compounds giving 50% inhibition of enzymatic activity)were determined.

C-Met Phosphorylation Cell-Based Assay

This test measures the ability of compounds to inhibit HGF stimulatedauto-phosphorylation of the c-Met/HGF receptor itself in a whole cellsystem.

MNNGHOS cell line expressing TPR-MET fusion protein were purchased fromATCC. The TPR-MET is the product of a chromosomal translocation placingthe TPR locus on chromosome 1 upstream of the MET gene on chromosome 7encoding for it's cytoplasmic region catalytic domain. Dimerization ofthe M_(r) 65,000 TPR-Met oncoprotein through a leucine zipper motifencoded by the TPR portion leads to constitutive activation of the metkinase. Constitutive autophosphorylation occurs on residuesTyr361/365/366 of TPR-Met. These residues are homologous toTyr1230/1234/1235 of MET which become phosphorylated upon dimerizationof the receptor upon HGF binding.

Inhibitor of c-Met formulated as 30 mM stocks in DMSO. For MNNGHOStreatments, cells, compounds were added to tissue culture media atindicated doses for 3 hours prior to cell lysis. Cells were lysed inice-cold lysis buffer containing 50 mM HEPES (pH 7.5), 150 mM NaCl, 1.5mM MgCl2, 10% glycerol, 1% Triton X-100, 1 mM4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, 200 μM sodiumorthovanadate, 1 mM sodium fluoride, 10 μg/ml of leupeptin, 10 μg/ml ofaprotinin/ml, 1 ug/ml of pepstatin and 50 ug/ml Na-p-Tosyl-L-lysinechloromethyl ketone hydrochloride.

Lysate were separated on 5-20% PAGE-SDS and immunoblots were performedusing Immobilon P polyvinylidene difluoride membranes (Amersham)according to the manufacturer's instructions for handling. The blotswere washed in Tris-buffered saline with 0.1% Tween 20 detergent (TBST).Tyr361/365/366 of TPR-Met were detected with polyclonal rabbitantibodies against tyrosine phosphorylated Met (Biosource International)and secondary antibodies anti-rabbit -horseradish peroxidase (Sigma) bychemiluminescence assays (Amersham, ECL) were performed according to themanufacturer's instructions and followed by film exposure. Signal wasquantitated by densitometry on Alpha-Imager. IC₅₀ values were defined asthe dose required to obtain 50% inhibition of the maximal HGF stimulatedphosphorylated c-Met levels.

In Vivo Solid Tumor Disease Model

This test measures the capacity of compounds to inhibit solid tumorgrowth.

Tumor xenografts were established in the flank of female athymic CD1mice (Charles River Inc.), by subcutaneous injection of 1×10⁶U87, A431or SKLMS cells/mouse. Once established, tumors were then seriallypassaged s.c. in nude mice hosts. Tumor fragments from these hostanimals were used in subsequent compound evaluation experiments. Forcompound evaluation experiments female nude mice weighing approximately20 g were implanted s.c. by surgical implantation with tumor fragmentsof 30 mg from donor tumors. When the tumors were approximately 100 mm insize (˜7-10 days following implantation), the animals were randomized aseparated into treatment and control groups. Each group contained 6-8tumor-bearing mice, each of which was ear-tagged and followedindividually throughout the experiment.

Mice were weighed and tumor measurements are taken by calipers threetimes weekly, starting on Day 1. These tumor measurements were convertedto tumor volume by the well-known formula (L+W/4)³4/3π. The experimentwas terminated when the control tumors reached a size of approximately1500 mm³. In this model, the change in mean tumor volume for a compoundtreated group/the change in mean tumor volume of the control group(non-treated or vehicle treated)×100 (ΔT/ΔC) was subtracted from 100 togive the percent tumor growth inhibition (%TGI) for each test compound.In addition to tumor volumes, body weight of animals were monitoredtwice weekly for up to 3 weeks.

The activities of a number of compounds according to the inventionmeasured by various assays are displayed in the following table, Table24. In the table, “a” indicates inhibitory activity at a concentrationof less than 50 nanomolar; “b” indicates inhibitory activity at aconcentration ≧50 but <250 nanomolar, “c” indicates inhibitory activityat ≧250 but <500 and “d” indicates inhibitory activity at aconcentration of ≧500 nanomolar; and “e” indicates no activity asmeasured by that assay.

TABLE 24 C-Met cell-based Y1230-34-35 tpr- Example Compound C-Met (enz.)VEGF(enz.) met inhibition No No (IC₅₀, μM) (IC₅₀, μM) (IC₅₀, μM) 1 8a ba a 2 8b b a b 3 8c b c b 5 8e b b b 7 8g b c b 9 8i b b c 10 8j b b b11 8k b d b 12 13a b a a 13 13b b a a 14 13c b b b 15 13d b a a 133 170ab b b 16 13e b a c 18 13g b b b 20 18a b d e 22 26a b b a 23 26b b a b24 26c b c d 25 26d b b e 26 26e b b e 27 26f b b e 28 31a b d e 29 31bc d e 35 8m b b a 36 8n b d b 37 8o b a a 40 8r b a b 75 13k b a a 14226f b a a 188 170c c d d 221 269a a d d

In the following table, Table 25, “a” indicates % TGI in the range of75-100; “b” indicates % TGI in the range of 50-74; “c” indicates % TGIin the range of 25-49, and “d” indicates % TGI in the range of 0-24.Regiment of administration was once daily.

TABLE 25 Dosage mg/kg Duration of Tumor Growth (once experiment Route ofInhibition Ex (Cpd) daily) Vehicle Tumor type (days) administration (%)1 (8a) 30 DMSO A431 14 IP d 30 DMSO A549 14 IP b 100 5% DMSO - 1%Tween-80 in water U87MG 14 PO c 15 DMSO MKN74 10 IP d 30 DMSO MKN74 10IP c 15 DMSO U87MG 10 IP c 30 DMSO U87MG 7 IP c 30 DMSO A431 14 IP c 30DMSO U87MG 14 IP c 30 DMSO SKLMS40 14 IP b 30 DMSO SW48 14 IP b 30 DMSOU87MG 14 IP  a* 30 DMSO HGT116 14 IP c 7 (8g) 30 DMSO SW48 14 IP c 30DMSO HCT116 14 IP b 12 (13a) 30 DMSO SW48 14 IP b 30 DMSO U87MG 14 IP b30 DMSO HST116 14 IP c 30 DMSO SW48 14 IP d 13 (13b) 30 DMSO A431 7 IP b30 DMSO SW48 14 IP d 30 DMSO U87MG 14 IP a 30 DMSO DU145 10 IP d 30 DMSOSKLMS40 10 IP b 37 (8o) 15 DMSO DU145 10 IP d 30 DMSO DU145 10 IP d 30DMSO A431 14 IP b 30 DMSO A549 14 IP c 15 50/50 DMSO: 40/60 PEG/0.2 NHCl in saline U87MG 10 IV b 30 50/50 DMSO: 40/60 PEG/0.2 N HCl in salineU87MG 10 IV c 15 (13d) 30 DMSO DU145 10 IP b 30 DMSO SKLMS40 10 IP b 30DMSO A431 14 IP b 30 DMSO A549 14 IP b 15 DMSO DU145 10 IP d 30 DMSODU145 10 IP d 15 50/50 DMS0: 40/60 PEG/0.2 N HCl in saline U87MG 10 IV b30 50/50 DMS0: 40/60 PEG/0.2 N HCl in saline U87MG 10 IV b 100 5% DMS0 -1% Tween-80 in water U87MG 14 PO a 30 DMSO U87MG 14 IP b 75 5% DMSO - 1%Tween-80 in water A549 12 PO c 50 5% DMSO - 1% Tween-80 in water A549 11PO c 75 5% DMSO - 1% Tween-80 in water A549 10 PO b 15 DMSO MKN74 10 IPc 30 DMSO MKN74 10 IP c 15 DMSO U87MG 10 IP b 30 DMSO U87MG 10 IP b 15DMSO HCT116 10 IP c 30 DMSO HCT116 10 IP c 75 (13k) 15 DMSO DU145 10 IPc 15 DMSO SKLMS40 10 IP b 100 5% DMSO - 1% Tween-80 in water U87MG 14 POb 30 DMSO U87MG 14 IP c 75 5% DMSO - 1% Tween-80 in water A549 12 PO b30 DMSO U87MG 10 IP c 15 DMSO U87MG 10 IP d 73 (13i) 100 5% DMSO - 1%Tween-80 in water U87MG 14 PO c 38 (8p) 30 DMSO A431 14 IP c 30 DMSOA549 14 IP c 39 (8g) 30 DMSO A549 14 IP b 148 (26l) 30 DMSO DU145 10 IPc 30 50/50 DMSO: 40/60 PEG/0.2 N HCl in saline U87MG 10 IP c 76 (13l) 755% DMSO - 1% Tween-80 in water A549 10 PO b 75 5% DMSO - 1% Tween-80 inwater DU145 10 PO c 30 DMSO A549 14 IP b 75 5% DMSO - 1% Tween-80 inwater A549 14 PO c 157 (195b) 30 DMSO A341 14 IP c 30 DMSO A549 14 IP c56 (55) 30 DMSO A549 12 IP c 63 (76c) 30 DMSO A549 10 IP b 30 DMSO DU14510 IP c 77 (13m) 30 DMSO A549 10 IP b 75 5% DMSO - 1% Tween-80 in waterA549 10 PO b 75 5% DMSO - 1% Tween-80 in water U87MG 14 PO b 75 5%DMS0 - 1% Tween-80 in water SKLMS40 6 PO d 201 (227) 30 DMSO A549 10 IPc 75 5% DMSO - 1% Tween-80 in water A549 10 PO c 81 (13q) 75 5% DMSO -1% Tween-80 in water SKLMS40 14 PO c 242 (310a) 75 5% DMSO - 1% Tween-80in water U87MG 14 PO a 75 5% DMSO - 1% Tween-80 in water HCT116 14 PO b243 (310b) 75 5% DMSO - 1% Tween-80 in water U87MG 14 PO b 75 5% DMSO -1% Tween-80 in water SKLMS40 11 PO b 137 (178) 75 0.5% CMC in acetatebuffer (pH 4.0) MDA-MB- 14 PO b 231 138 (179) 75 0.5% CMC in acetatebuffer (pH 4.0) MDA-MB- 14 PO b 231 a* - greater than 100% tumor growthinhibition (i.e., tumor shrinkage)

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1. A compound of the formula (A)

and pharmaceutically acceptable salts thereof, wherein T is selectedfrom the group consisting of arylalkyl, cycloalkyl, heterocyclyl, aryland heteroaryl, wherein each of said arylalkyl, cycloalkyl,heterocyclyl, aryl and heteroaryl is optionally substituted with 1 to 3independently selected R²⁰; each R²⁰ is independently selected from thegroup consisting of —H, halogen, trihalomethyl, —CN, —NO₂, —NH₂, —OR¹⁷,—OCF₃, —NR¹⁷R¹⁸, —S(O)₀₋₂R¹⁷, —S(O)₂NR¹⁷R¹⁷, —C(O)OR¹⁷, —C(O)NR¹⁷R¹⁷,—N(R¹⁷)SO₂R¹⁷, —N(R¹⁷)C(O)R¹⁷, —N(R¹⁷)C(O)OR¹⁷, —C(O)R¹⁷, —C(O)SR¹⁷,C₁-C₄ alkoxy, C₁-C₄ alkylthio, —O(CH₂)_(n)aryl, —O(CH₂)_(n)heteroaryl,—(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄alkylcarbonyl, C₁-₄ alkoxy, an amino optionally substituted by C₁₋₄alkyl optionally substituted by C₁₋₄ alkoxy and a saturated orunsaturated three- to seven-membered carboxyclic or heterocyclic group,wherein T² is selected from the group consisting of —OH, —OMe, —OEt,—NH₂, —NHMe, —NMe₂, —NHEt and —NEt₂, and wherein the aryl, heteroaryl,C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl are optionallysubstituted; W is selected from the group consisting of O, S, NH andNMe; Z is selected from the group consisting of O, or S and NH; X and X¹are independently selected from the group consisting of H, C₁-C₆ alkyl,halo, cyano, or nitro, wherein C₁-C₆ alkyl is optionally substituted, orX and X¹ taken together with the atom to which they are attached, form aC₃-C₇ cycloalkyl; R¹, R², R³ and R⁴ independently represent hydrogen,halo, trihalomethyl, —CN, —NO₂, —OR¹⁷, —NR¹⁷R¹⁸, —C(O)OR¹⁷, —C(O)R¹⁷,C₁-C₄ alkoxy, C₁C₄ alkylthio, C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl areoptionally substituted; R¹⁷ is selected from the group consisting of Hand R¹⁸; R¹⁸ is selected from the group consisting of a (C₁-C₆)alkyl, anaryl, a aryl(C₁-C₆)alkyl, a heterocyclyl and a heterocyclyl(C₁-C₆)alkyl,each of which is optionally substituted, or R¹⁷ and R¹⁸, taken togetherwith a common nitrogen to which they are attached, form an optionallysubstituted five- to seven-membered heterocyclyl, the optionallysubstituted five- to seven-membered heterocyclyl optionally containingat least one additional annular heteroatom selected from the groupconsisting of N, O, S and P; R¹⁶ is selected from the group consistingof —H, —CN, —(CH₂)₀₋₅(aryl), —(CH₂)₀₋₅(heteroaryl), C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, —CH₂(CH₂)₀₋₄-T², an optionally substituted C₁₋₄alkylcarbonyl, and a saturated or unsaturated three- to seven-memberedcarboxyclic or heterocyclic group, wherein T² is selected from the groupconsisting of —OH, —OMe, —OEt, —NH₂, —NHMe, —NMe₂, —NHEt and —NEt₂, andwherein the aryl, heteroaryl, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆alkynyl are optionally substituted; Q is S; D is C-E, C—C₁-C₆ alkyl orCH, wherein the C₁-C₆ alkyl is optionally substituted by 1 to 5independently selected R³⁸; L is CR, wherein R is selected from thegroup consisting of —H, halo, —CN, C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl, and C₂-C₆ alkynyl areoptionally substituted; and E is selected from the group consisting ofE¹, E² and E³, wherein E¹ is selected from the group consisting ofC₃-C₁₀ cycloalkyl, —C(O)NR⁴²R⁴³, —NR⁴²R⁴³, —NR⁴²C(═O)R⁴³, —SO₂R⁴²,—SO₂NR⁴²R⁴³, —NR³⁷SO₂R⁴², —C(═NR⁴²)NR³⁷R⁴³, —C(O)R⁴², —CO₂R⁴²,—C(O)(heterocyclyl), —C(O)(C₆-C₁₀ aryl), —C(O)(heteroaryl), —Y—(C₆-C₁₀aryl), —Y-(heteroaryl), —Y—(5-10 membered heterocyclic), —NR^(6a)R^(6b), —NR^(6a)SO₂R^(6b), —NR^(6a)C(O)R^(6b)—OC(O)R^(6b), —OR^(6a),—SR^(6a), —S(O)R^(6a), —SO₂R^(6a), —SO₂NR^(6a)R^(6b), —COR^(6a),—CO₂R^(6a), —CONR^(6a)R^(6b), —(C₁-C₄)fluoroalkyl and—(C₁-C₄)fluoroalkoxy, —(CZ³Z⁴)_(a)CN, wherein n is an integer rangingfrom 0 to 6, and the aforementioned E^(l) groups are substituted by 1 to5 independently selected R³⁸, or E¹ is selected from a moiety selectedfrom the group consisting of —(CZ³Z⁴)_(a)-aryl,—(CZ³Z⁴)_(a)-heterocycle, (C₂-C₆)alkynyl,—(CZ³Z⁴)_(a)—(C₃-C₆)cycloalkyl, —(CZ³Z⁴)_(a)—(C₅-C₆)cycloalkenyl and(C₂-C₆) alkenyl, which is substituted with 1 to 3 independently selectedY² groups, where a is 0, 1, 2, or 3, and wherein when a is 2 or 3, theCZ³Z⁴ units may be the same or different; wherein each R³⁸ isindependently selected from cyano, nitro, azido, —OC(O)R⁴⁰, —OC(O)OR⁴⁰,—NR³⁶C(O)R³⁹, —NR³⁶R³⁹, —OH, —SO₂NR³⁶R³⁹, —(CH₂)_(j)(CH₂)_(i)NR³⁶R³⁹,—S(O)_(j)(C₁-C₆ alkyl), —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹,—(CH₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁷C(O)R⁴⁰,—(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i)OR³⁷—(CH₂)_(i)NR³⁹(CH₂)_(i)S(O)_(j)(C₁-C₆ alkyl),—(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶, —SO₂(CH₂)_(n)(C₆-C₁₀ aryl),—SO₂(CH₂)_(n)(5-10 membered heterocyclyl), —(CH₂)_(n)NR³⁶R³⁹,—NR³⁷SO₂NR³⁶R³⁹, SO₂R³⁶ and C₁-C₆ alkylamino, wherein j is an integerranging from 0 to 2, n is an integer ranging from 0 to 6, i is aninteger ranging from 0 to 6, the —(CH₂)_(i)- and —(CH₂)_(n)- moieties ofthe foregoing R³⁸ groups optionally include a carbon-carbon double ortriple bond where n is an integer between 2 and 6, and the alkyl, aryl,and heterocyclyl moieties of the foregoing R³⁸ groups are optionallysubstituted by one or more substituents independently selected from thegroup consisting of halo, cyano, nitro, trifluoromethyl, azido, —OH,—C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹,—(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀aryl), —(CH₂)_(n)(5-10 membered heterocyclyl), —(CH₂)_(n)O(CH₂)_(i)²OR³⁷, and —(CH₂)_(n)OR³⁷, wherein n is an integer ranging from 0 to 6and i² is an integer ranging from 2 to 6; each R⁴² and R⁴³ isindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₆heteroalkyl, —Y—(C₃-C₁₀ cycloalkyl), —Y—(C₆-C₁₀ aryl), —Y—(C₆-C₁₀heteroaryl), —Y—(5-10 membered heterocyclic), —Y—O—Y¹—OR³⁷, —Y¹—CO₂—R³⁷,and —Y—OR³⁷, wherein the alkyl, heteroalkyl, cycloalkyl, aryl,heteroaryl and heterocyclic moieties of the foregoing R⁴² and R⁴³ groupsare substituted by 1 or more substituents independently selected fromR⁴⁴, wherein Y is a bond or is —(C(R³⁷)(H))_(n) ², n²is an integerranging from 1 to 6, and Y¹ is —(C(R³⁷)(H))_(n), or R⁴² and R⁴³ takentogether with the nitrogen to which they are attached form a C₅-C₉heterocyclyl ring or a heteroaryl ring, wherein said ring is substitutedby 1 to 5 independently selected R⁴⁴ substituents, with the proviso thatR⁴² and R⁴³ are not both bonded to the nitrogen directly through anoxygen; each R⁴⁴ is independently selected from the group consisting ofcyano, nitro, azido, —OC(O)R⁴⁰, —OC(O)OR⁴⁰, —NR³⁶C(O)R³⁹, —NR³⁶R³⁹,—SO₂NR³⁶R³⁹, —SO₂R³⁶, —NR³⁶SO₂R³⁹, —NR,³⁶SO₂NR³⁷R⁴¹, —C₁-C₆ alkylamino,—(CH₂)_(j)O(CH₂)_(i) ²NR³⁶R³⁹, —S(O)_(j)(C₁-C₆ alkyl),—C(O)(CH₂)_(n)(C₆-C₁₀ aryl), —C(O)(CH₂)_(n)(5 to 10 memberedheterocyclic), —(CH₂)_(j)NR³⁹(CH₂)_(i) ²NR³⁶R³⁹,—(CH₂)_(j)NR³⁹CH₂C(O)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH²)_(i) ²NR³⁷C(O)R⁴⁰,—(CH₂)_(j)NR³⁹(CH₂)_(n)O(CH₂)_(i) ²OR³⁷, —(CH₂)_(j)NR³⁹(CH₂)_(i)²S(O)_(j)(C₁-C₆ alkyl), —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,—SO₂(CH₂)_(n)(C₆-C₁₀aryl), and —SO₂(CH₂)_(n)(5 to 10 memberedheterocyclic) wherein, j is an integer from 0 to 2, n is an integer from0 to 6 and i² is an integer ranging from 2 to 6, the —(CH₂)_(i) ²and—(CH₂)_(n)moieties of the foregoing R⁴⁴ groups optionally include acarbon-carbon double or triple bond wherein n is an integer from 2 to 6,and the alkyl, aryl and heterocyclic moieties of the foregoing R⁴⁴groups are optionally substituted by 1 or more substituentsindependently selected from the group consisting of halo, cyano, nitro,trifluoromethyl, azido, —OH, —C(O)R⁴⁰,—C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰,—NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, —SO₂R³⁶, —SO₂NR³⁶R³⁹,C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5 to10 membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i) ²OR³⁷ and—(CH₂)_(n)OR³⁷, wherein n is an integer from 0 to 6 and i² is an integerfrom 2 to 6; and each R⁴⁰is independently selected from H, C₁-C₁₀ alkyl,—(CH₂)_(n)(C₆-C₁₀ aryl), C₃-C₁₀ cycloalkyl, and —(CH₂)_(n)(5-10 memberedheterocyclic), wherein n is an integer ranging from 0 to 6; each R³⁶ andR³⁹ is independently selected from the group consisting of H, —OH, C₁-C₆alkyl, C₃-C₁₀ cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-1 0membered heterocyclic), —(CH₂)_(n)O(CH₂)_(i)OR³⁷ and—(CH₂)_(n)O(CH₂)_(i) ²OR³⁷, wherein n is an integer ranging from 0 to 6and i² is an integer ranging from 2 to 6, and the alkyl, aryl andheterocyclic moieties of the foregoing R³⁶ and R³⁹ groups are optionallysubstituted by one or more substituents independently selected from —OH,halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁴⁰, —C(O)OR⁴⁰,—OC(O)OR⁴⁰, —NR³⁷C(O)R⁴¹, —C(O)NR³⁷R⁴¹, —NR³⁷R⁴¹, -C₁-C₆ alkyl,—(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5 to 10 membered heterocyclic),—(CH₂)_(n)O(CH₂)_(i) ²OR³⁷and —(CH₂)_(n)OR³⁷, wherein n is an integerranging from 0 to 6 and i²is an integer ranging from 2 to 6, with theproviso that when R³⁶ and R³⁹ are both attached to the same nitrogen,then R³⁶ and R³⁹ are not both bonded to the nitrogen directly through anoxygen; each R³⁷ and R⁴¹ is independently selected from the groupconsisting of H, OR³⁶, C₁-C₆ alkyl and C₃-C₁₀ cycloalkyl; each R^(6a)and R^(6b) is independently selected from the group consisting ofhydrogen, —(CZ⁵Z⁶)_(u)—(C₃-C₆)cycloalkyl,—(CZ⁵Z⁶)_(u)—(C₅-C₆)cycloalkenyl, —(CZ⁵Z⁶)_(u)-aryl,—(CZ⁵Z⁶)_(u)-heteroaryl, —(CZ⁵Z⁶)_(u)-heterocycle, (C₂-C₆)alkenyl, and(C₁-C₆)alkyl, each of which is substituted with 1 to 3 independentlyselected Y³ groups, where u is 0,1, 2, or 3, and wherein when u is 2 or3, the CZ⁵Z⁶ units may be the same or different, or R⁶a and R⁶b takentogether with adjacent atoms can form a heterocycle; each Z³, Z⁴, Z⁵ andZ⁶ is independently selected from the group consisting of H, F and(C₁-C₆)alkyl, or each Z³ and Z⁴, or Z⁵ and Z⁶ are selected together toform a carbocycle, or two Z³ groups on adjacent carbon atoms areselected together to optionally form a carbocycle; each Y² isindependently selected from the group consisting of nitro, tetrazolyl,guanidino, amidino, methylguanidino, azido, —OC(O)NH₂, —OC(O) NHZ⁷,—OC(O)NZ⁷Z⁸, —NHC(O)Z⁷, —NHC(O)NH₂, —NHC(O)NHZ⁷, —NHC(O)NZ⁷Z⁸, —P(O)₃H₂,—P(O)₃(Z⁷)₂, —S(O)₃H, —S(O)Z⁷, —S(O)₂Z⁷, —S(O)₃Z⁷, —OH, —NH₂, —NHZ⁷,—NZ⁷Z⁸, —C(═NH)NH₂,—C(═NOH)NH₂, —Nmorpholino,)—(CZ⁹Z¹⁰)_(r)NH₂,)—(CZ⁹Z¹⁰)_(r)NHZ³,—(CZ⁹Z¹⁰)_(r)NZ⁷Z⁸,)—X⁶(CZ⁹Z¹⁰)_(r)—(C₃-C₈)cycloalkyl,)—X⁶(CZ⁹Z¹°_(r)(C₅-C₈)cycloalkenyl,)—X⁶(CZ⁹Z¹° _(r)aryl and—X⁶(CZ⁹Z¹⁰)_(r—)heterocycle, each Y³ is independently selected from thegroup consisting of nitro, tetrazolyl, guanidino, amidino,methylguanidino, azido, —OC(O)NH₂, —OC(O)NHZ⁷, —OC(O)NZ⁷Z⁸, —NHC(O)Z⁷,—NHC(O)NH₂, —NHC(O)NHZ⁷, —NHC(O)NZ⁷Z⁸, —P(O)₃H₂, —P(0)₃(Z⁷)₂, —S(O)₃H,—S(O)Z⁷, —S(O)₂Z⁷, —S(O)₃Z⁷, —OH, —NH₂, —NHZ⁷, —NZ⁷Z⁸, —C(=NH)NH₂,——C(=NOH)NH₂, —Nmorpholino,)—(CZ⁹Z¹⁰)_(r)NH₂,)—(CZ⁹Z¹⁰)_(r)NHZ³,—(CZ⁹Z¹⁰)_(r)NZ⁷Z⁸,—X⁶(CZ⁹Z¹⁰)_(r)—(C₃C₈)cycloalkyl,—X(CZ⁹Z¹⁰)_(r)(C₅-C₈)cycloalkenyl,—X⁶(CZ⁹Z¹⁰)_(r)-aryl and—X⁶(CZ⁹Z¹⁰)_(r)-heterocycle, wherein r is 1, 2, 3 or 4; X⁶ is selectedfrom the group consisting of S, NH, —C(O)—, —C(O)NH—, —C(O)O—, —S(O)—,—S(O)₂— and —S(O)₃—; Z⁷ and Z⁸ are independently selected from the groupconsisting of an alkyl of 1 to 12 carbon atoms, an alkenyl of 2 to 12carbon atoms, an alkynyl of 2 to 12 carbon atoms, a cycloalkyl of 3 to 8carbon atoms, a cycloalkenyl of 5 to 8 carbon atoms, an aryl of 6 to 14carbon atoms, a heterocycle of 5 to 14 ring atoms, an aralkyl of 7 to 15carbon atoms, and a heteroaralkyl of 5 to 14 ring atoms, or Z⁷ and Z⁸together may optionally form a heterocycle; Z⁹ and Z¹⁰ are independentlyselected from the group consisting of H, F, a (C_(i)-C₁₂)alkyl, a(C₆-C₁₄) aryl, a (C₅-C₁₄)heteroaryl, a (C₇-C₁₅)aralkyl and a(C₅-C₁₄)heteroaralkyl, or Z⁹ and Z¹⁰ are taken together form acarbocycle, or two Z⁹ groups on adjacent carbon atoms are taken togetherto form a carbocycle; or any two Y² or Y³ groups attached to adjacentcarbon atoms may be taken together to be —O[C(Z⁹)(Z¹⁰)]_(r)O or—O[C(Z⁹)(Z¹⁰)]_(r+1), or any two Y² or Y³ groups attached to the same oradjacent carbon atoms may be selected together to form a carbocycle orheterocycle; and wherein any of the above-mentioned substituentscomprising a CH₃ (methyl), CH₂ (methylene), or CH (methine) group whichis not attached to a halogen, SO or SO₂ group or to a N, O or S atomoptionally bears on said group a substituent selected from hydroxy,halogen, (C₁- C₄) alkyl, (C₁-C₄)alkoxy and an—N[(C₁-C₄)alkyl][(C_(I)-C₄)alkyl]; E² is —C≡C-(CR⁴⁵R⁴⁵)_(n) ²-R⁴⁶, n² isan integer ranging from 1 to 6; R⁴⁵ is independently selected from thegroup consisting of H, a (C₁-C₆)alkyl and a (C₃- C₈) cycloalkyl; R⁴⁶ isselected from the group consisting of heterocyclyl,—N(R⁴⁷)—C(O)—N(R⁴⁷)(R⁴⁸), —N(R⁴⁷)—C(S)—N(R⁴⁷)(R⁴⁸),—N(R⁴⁷)—C(O)—OR⁴⁸,—N(R⁴⁷)—C(O)-(CH₂)_(n)—R⁴⁸, —N(R⁴⁷)—SO₂R⁴⁷, —(CH₂)_(n)NR⁴⁷R⁴⁸,—(CH₂)_(n)SR⁴⁹, —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, OC(O)R⁴⁹,OC(O)0R⁴⁹; R⁴⁷ and R⁴⁸ are independently selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₃-C₈) cycloalkyl, heterocyclyl,—(CH₂)_(n)NR⁵⁰R⁵¹, —(CH₂)_(n) 0R⁵⁰, —(CH₂)_(n)C(O)R⁴⁹, —C(O)₂R⁴⁹,(CH₂),SR⁴⁹, —(CH₂)_(n)S(O)R⁴⁹, —(CH₂)_(n)S(O)₂R⁴⁹, —(CH₂),R⁴⁹,—(CH₂),CN, aryl optionally substituted with one or more substituentsselected from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,(C₁-C₆)alkyl, —CN, —(CH₂)_(n) 0R⁴⁹, —(CH₂)_(n)heterocyclyl,—(CH₂)_(n)heteroaryl, —SO₂R⁵⁰ and —(CH₂)_(N)NR⁵⁰R⁵¹, and heteroaryloptionally substituted with one or more substituents selected from thegroup consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN,—(CH₂)_(n)OR⁴⁹, —(CH₂)_(n)heterocyclyl, —(CH₂)_(n)heteroaryl, —SO₂R⁵⁰and —(CH₂)_(n) NR⁵⁰R⁵¹, or R⁴⁷ and R⁴⁸, together with the atom to whichthey are attached, form a 3-8 membered ring; R⁴⁹ is selected from thegroup consisting of (C₁-C₆)alkyl, (C₃-C₈)cycloalkyl, heterocyclyl(C₁-C₆) alkylene, aryl(C₁-C₆)alkylene wherein the aryl is optionallysubstituted with one or more substituents selected from the groupconsisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN,—SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, heteroaryl(C₁-C₆)alkylene wherein theheteroaryl is optionally substituted with one or more substituentsselected from the group consisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂,(C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, aryl optionallysubstituted with one or more substituents selected from the groupconsisting of halo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN,—SO₂R⁵⁰ and —(CH₂)_(n)NR⁵⁰R⁵¹, and heteroaryl optionally substitutedwith one or more substituents selected from the group consisting ofhalo, —CF₃, (C₁-C₆)alkoxy, —NO₂, (C₁-C₆)alkyl, —CN, —SO₂R⁵⁰ and—(CH₂)_(n)NR⁵⁰R⁵¹; R⁵⁰ and R⁵¹ are independently selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₃-C₈) cycloalkyl and —C(O)R⁴⁵, or R⁵⁰and R⁵¹, together with the atom to which they are attached, form a 3-8membered ring; and E³ is the group defined by—(Z₁₁)-(Z¹²)_(m)—(Z¹³)_(m1), wherein Z¹¹ is heterocyclyl orheterocyclylene; Z¹² is selected from the group consisting of OC(O) andOC(S); Z¹³ is selected from the group consisting of heterocyclyl,aralkyl, N(H)R⁵², (C₁-C₃)alkyl, OR⁵², halo, S(O)₂R⁵⁶,(C₁-C₃)hydroxyalkyl and (C₁-C₃)haloalkyl; m is 0 or 1; ml is 0 or 1; R⁵²is selected from the group consisting of H, —(CH₂)_(q)S(O)₂R⁵⁴,R⁵⁵NR⁵³R⁵³,(C₁-C₃)alkyl, —(CH₂)_(q)OR⁵³, —C(O)R⁵⁴ and —C(O)OR⁵³; q is 0,1, 2, 3 or 4; R⁵³ is (C₁-C₃)alkyl; R⁵⁴ is (C₁-C₃)alkyl or N(H)R⁵³; R⁵⁵is (C₁-C₆) alkyl; and R⁵⁶ is selected from the group consisting of NH₂,(C₁-C₃)alkyl and OR⁵².
 2. The compound according to claim 1, wherein Tis aryl or heteroaryl, wherein each of said aryl and heteroaryl isoptionally substituted with 1 to 3 independently selected R²⁰.
 3. Thecompound according to claim 1, wherein T is selected from the groupconsisting of arylalkyl, cycloalkyl and heterocyclyl, wherein each ofsaid arylalkyl, cycloalkyl and heterocyclyl is optionally substitutedwith 1 to 3 independently selected R^(20.)
 4. The compound according toclaim 1, wherein W is O.
 5. The compound according to claim 1, wherein Zis S or O.
 6. The compound according to claim 1, wherein X and X¹ areboth H.
 7. The compound according to claim 1, wherein R¹ is H orhalogen.
 8. The compound according to claim 1, wherein R², R³ and R⁴ areeach H.
 9. The compound according to claim 1, wherein D is CH.
 10. Thecompound according to claim 1, wherein R is H or halogen.
 11. Thecompound according to claim 1, wherein E is selected from the groupconsisting of E¹ and E².
 12. The compound according to claim 1, whereinE is E¹.
 13. The compound according to claim 1, wherein E is E¹, whereinE^(l) is selected from the group consisting of —C(O)NR⁴²R⁴³,—SO₂NR⁴²R⁴³, C(═NR⁴²)NR³⁷R⁴³, —CO₂R⁴², —C(O)(heterocyclyl),—C(O)(heteroaryl), —Y—(C₆-C₁₀ membered heterocyclic),—SR^(6a),—S(O)R^(6a), —SO₂R^(6a), wherein each of said E^(l) aresubstituted with 1 to 5 independently selected R³⁸.
 14. The compoundaccording to claim 1, wherein R³⁸ is selected from the group consistingof —NR³⁶C(O)R³⁹, —NR³⁶R³⁹, —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,—S(O),_(j)(C₁-C₆alkyl), —(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(C₂)_(n)R³⁶,—(CH₂)_(n)NR³⁶R³⁹, wherein j is an integer ranging from 0 to 2, n is aninteger ranging from 0 to 6, i is an integer ranging from 1 to 6, the—(CH₂)_(i)- and —(CH₂)_(n)-moieties of the foregoing R³⁸ groupsoptionally include a carbon-carbon double or triple bond where n is aninteger between 2 and 6, and the alkyl, moieties of the foregoing R³⁸groups are optionally substituted by one or more substituentsindependently selected from the group consisting of halo, cyano, nitro,trifluoromethyl, azido, —OH, —C(O)R⁴, —C(O)OR⁴⁰, —OC(O)R⁴⁰, OC(O)OR⁴⁰,—NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 memberedheterocyclyl), —(CH₂)_(n)O(CH₂)_(i) ²OR³⁷, and —(CH₂)_(n) 0R³⁷, whereinn is an integer ranging from 0 to 6 and i² is an integer ranging from 2to
 6. 15. The compound according to claim 1, wherein each R⁴² and R⁴³independently selected from the group consisting of —Y—(C₃-C₁₀cycloalkyl), —Y—(C₆-C₁₀ aryl), —Y—(C₆-C₁₀ heteroaryl) and —Y—(5 to 10membered heterocyclic), wherein the cycloalkyl, aryl, heteroaryl andheterocyclic moieties of the foregoing R⁴² and R⁴³ groups aresubstituted by 1 or more substituents independently selected from R44.16. The compound according to claim 1, wherein one of R⁴² and R⁴³ is—(C₆-C₁₀ heteroaryl) or —Y—(5 to 10 membered heterocyclic).
 17. Thecompound according to claim 1, wherein Y is a bond.
 18. The compoundaccording to claim 1, wherein R⁴² and R⁴³ taken together with thenitrogen to which they are attached form a C₅-C₉ heterocyclyl ring or aheteroaryl ring, wherein said ring is optionally substituted by 1 to 5independently selected R⁴⁴ substituents, with the proviso that R⁴² andR⁴³ are not both bonded to the nitrogen directly through an oxygen. 19.The compound according to claim 1, wherein each R³⁶ and R³⁹ isindependently selected from the group consisting of H, C₁-C₆alkyl,—(CH₂)_(n)(5 to 10 membered heterocyclic) and —(CH₂)_(n)OR³⁷, wherein nis an integer ranging from 0 to 6 and i is an integer ranging from 2 to6, with the proviso that when R³⁶ and R³⁹ are both attached to the samenitrogen, then R³⁶ and R³⁹ are not both bonded to the nitrogen directlythrough an oxygen.
 20. The compound according to claim 1, wherein R^(6a)is selected from the group consisting of —(CZ⁵Z⁶)_(u)-aryl,—(CZ⁵Z⁶)_(u)-heteroaryl and C₁-C₆alkyl, each of which is substitutedwith 1 to 3 independently selected Y³ groups, wherein u is 0, 1, 2 or 3,and wherein when u is 2 or 3, the CZ⁵Z⁶ units may be the same ordifferent.
 21. The compound according to claim 1, wherein Y² is —OH. 22.The compound according to claim 1, wherein E² is —C≡C—(CR⁴⁵R⁴⁵)_(n)-^(R)⁴⁶, wherein n is an integer ranging from 1 to
 6. 23. The compoundaccording to claim 1, represented by the formula A-0:

and pharmaceutically acceptable salts thereof, wherein Z is O or S; Xand X¹ are independently selected from the group consisting of H, C₁-C₆alkyl, halo, cyano and nitro, wherein C₁-C₆ alkyl is optionallysubstituted; R¹,R²,R³ and R⁴ are independently selected from the groupconsisting of hydrogen, halo, trihalomethyl, —OR¹⁷, C₁-C₆ alkyl, C₂-C₆alkenyl or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆alkynyl are optionally substituted; Q is S; D is CH or C(C₁-C₆ alkyl),wherein the C₁-C₆ alkyl is optionally substituted by 1 to 5independently selected R³⁸; L is CR, wherein R is H, halo, —CN, C₁-C₆alkyl, C₂-C₆ alkenyl, or C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted; and R⁷ is—C(═O)NR⁹R¹⁰, —C(═O)(C₆-C₁₀aryl), —C(═O)(heterocyclyl),—C(═O)(heteroaryl), —Y—(C₆ C₁₀aryl), —Y—(5 to 10 membered heterocyclyl),—Y—(heteroaryl), —S-aryl, —S-C₁-C₆ alkyl, —SO—C₁-C₆ alkyl, —SO₂-C₁-C₆alkyl, —NR⁹R¹⁰, —SO₂NR⁹R¹⁰ or CO₂R⁹, wherein C₁-C₆ alkyl, aryl,heterocycle and heteroaryl are each independently substituted with 1 to5 independently selected R³⁸; R⁹ and R¹⁰ are independently selected fromC₁-C₆ alkyl, —Y—(C₃-C₁₀cycloalkyl), —Y—(C₆-C₁₀aryl), —Y—(5 to 10membered heterocyclyl), —Y—(C₆-C₁₀heteroaryl), —Y—O—Y¹—O—R¹¹,—Y¹-CO₂-R¹¹, and Y¹—O—R¹¹, wherein C₁-C₆ alkyl, cycloalkyl, aryl,heterocycle, and heteroaryl are each substituted with 1 or more R⁴⁴, orR⁹ and R¹⁰ taken together with the nitrogen to which they are attachedform a C₅-C₉ heterocyclyl ring or a heteroaryl ring, wherein said ringis substituted with 1 or more R⁴⁴; Y is a bond or is —(C(R¹¹)(H))_(t)—,wherein t is an integer from 1 to 6; Y¹ is —(C(R¹¹)(H))_(t)—, R¹¹ ateach occurrence is independently H or C_(I)-C₆ alkyl, each R²⁰ isindependently selected from the group consisting of hydrogen, halo,trihalomethyl, OR¹⁷, C₁-C₆ alkyl, C₂-C₆ alkenyl or C₂-C₆ alkynyl,wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl are optionallysubstituted, and each R¹⁷ is an independently selected C₁-C₆alkyl,wherein said C₁-C₆alkyl is optionally substituted.
 24. The compoundaccording to claim 23, wherein X and X¹ are both hydrogen.
 25. Thecompound according to claim 23, wherein R¹ is fluorine.
 26. The compoundaccording to claim 23, wherein R²⁰ is —OR¹⁷.
 27. The compound accordingto claim 23, wherein L is CH.
 28. The compound according to claim 23,wherein R⁷ is —CONR⁹R¹⁰.
 29. The compound according to claim 23, whereinR⁷ is Y-Heteroaryl.
 30. The compound according to claim 23, wherein Z issulfur.
 31. The compound according to claim 1, represented by theformula A-1:

and pharmaceutically acceptable salts thereof, wherein R¹ is selectedfrom the group consisting of hydrogen, halo, C₁-C₆ alkenyl or C₂-C₆alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl areoptionally substituted; X and X¹ are independently selected from thegroup consisting of H and C₁-C₆ alkyl, wherein C₁-C₆ alkyl is optionallysubstituted, or X and X¹ taken together with the atom to which they areattached, form a C₃-C₇ cycloalkyl; R⁷ is C(═O)NR⁹R¹⁰,—C(═O)(C₆-C₁₀aryl), —C(═O)(heterocyclyl), —C(═O)(heteroaryl),—Y—(C₆-C₁₀aryl), —Y—(5 to 10 membered heterocyclyl), —Y—(heteroaryl),—SR^(6a), —S-aryl, —S -(heteroaryl), —S—C₁-C₆ alkyl, —SO—C₁-C₆ alkyl,—SO₂—C₁-C₆ alkyl, —NR⁹R¹⁰, —SO₂NR⁹R¹⁰, CO₂R⁹, —C≡C—(CR⁴⁵R⁴⁵)_(n—R) ⁴⁶ or—C(═NR⁴²)NR³⁷R⁴³, wherein n is an integer ranging from 0 to 6 andwherein C₁-C₆ alkyl, aryl, heterocycle and heteroaryl are eachindependently substituted with 1 to 5 independently selected R³⁸; R⁹ andR¹⁰ are independently selected from C₁-C₆ alkyl, —Y—(C₃-C₁₀cycloalkyl),—(C₁-C₆ heteroalkyl), —Y—(C₆-C₁₀aryl), —Y—(5 to 10 memberedheterocyclyl), —Y—(C₆-C₁₀heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—¹¹, and—Y—O—R¹¹, wherein said C₁-C₆ alkyl, heteroalkyl, cycloalkyl, aryl,heterocycle, and heteroaryl are each substituted with one or moreindependently selected R⁴⁴, or R⁹ and R¹⁰ taken together with thenitrogen to which they are attached form a C₅-C₉ heterocyclyl ring or aheteroaryl ring, wherein said ring is substituted with 1 to 5independently selected R⁴⁴; each R²⁰ is independently selected from thegroup consisting of H, halo, —OR¹⁷ and —C(O)OR¹⁷; Y is a bond or is—(C(R¹¹)(H))_(t)—, wherein t is an integer from 1 to 6; Y¹ is—(C(R¹¹)(H))_(t)—, and R¹¹ at each occurrence is independently H orC₁-C₆ alkyl.
 32. The compound according to claim 31, wherein R¹ isfluorine.
 33. The compound according to claim 31, wherein R⁷ is selectedfrom the group consisting of —C(═O)NR⁹R¹⁰, —Y—(C₆-C₁₀ aryl),—Y—(heteroaryl) and —S—C₁-C₆ alkyl, wherein said —Y—(aryl),—Y-(heteroaryl) and —S—C₁-C₆ alkyl are substituted with 1 to 5independently selected R³⁸.
 34. The compound according to claim 31,wherein R⁷ is —C(═O)NR⁹R¹⁰, substituted with one or more independentlyselected R³⁸.
 35. The compound according to claim 31, wherein R⁷ is—Y—(C₆-C₁₀aryl), substituted with 1 to 5 independently selected R³⁸. 36.The compound according to claim 31, wherein R³⁸ is selected from thegroup consisting of —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,—(CH₂)_(j)NR³⁹(CH)₂)_(i)NR³⁶R³⁹, and —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,wherein n is an integer ranging from 0 to 6, j is an integer rangingfrom 0 to 2, and i is an integer ranging from 1 to
 6. 37. The compoundaccording to claim 31, wherein R⁹ and R¹⁰ are independently selectedfrom the group consisting of C₁-C₆ alkyl, —C₁-C₆ heteroalkyl,—Y—(C₆-C₁₀aryl), —Y-(5 to 10 membered heterocyclyl),—Y—(C₆-C₁₀heteroaryl), and —Y—O—R¹¹, wherein a C₁-C₆ alkyl, C₁-C₆heteroalkyl, aryl, heterocyclcyl and heteroaryl are each substitutedwith 1 or more independently selected R⁴⁴.
 38. The compound according toclaim 31, wherein R³⁶ is selected from the group consisting of H, C₁-C₆alkyl, —(CH₂)_(n)OR³⁷ and —(CH₂)_(n)(5 to 10 membered heterocyclyl). 39.The compound according to claim 31, wherein each of R³⁷ and R³⁹ isindependently H or C₁-C₆ alkyl.
 40. The compound according to claim 31,wherein R²⁰ is selected from the group consisting of H, halogen, —OR¹⁷and —C(O)OR¹⁷.
 41. The compound according to claim 31, wherein R¹⁷ is Hor C₁-C₆ alkyl.
 42. The compound according to claim 33, wherein NR⁹R¹⁰is selected from the group consisting of:


43. The compound according to claim 31, wherein X and X¹ are both H. 44.The compound according to claim 43, wherein R¹⁷ is selected from thegroup consisting of H and C₁-C₆ alkyl.
 45. The compound according toclaim 1, represented by the formula A-4:

and pharmaceutically acceptable salts thereof, wherein Z is O or S; Xand X¹ are independently selected from the group consisting of H, C₁-C₆alkyl, halo, cyano and nitro, wherein C₁-C₆ alkyl is optionallysubstituted; R¹, R², R³, R⁴, R⁵ and R⁶ are independently selected fromthe group consisting of hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl and NR¹⁷R¹⁸, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆alkynyl are optionally substituted; R¹⁷ and R¹⁸ are independentlyC₁-C₆alkyl; Q is S; D is CH or C(C₁-C₆ alkyl), wherein the C₁-C₆ alkylis optionally substituted by 1 to 5 independently selected R³⁸; L is CR,wherein R is selected from the group consisting of H, halo, —CN, C ₁-C₆alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆alkenyl, and C₂-C₆ alkynyl are optionally substituted; and R¹³ isheterocyclyl or heteroaryl, wherein heterocyclyl and heteroaryl aresubstituted with 1 to 5 independently selected R³⁸; Y is a bond or is—(C(R¹¹)(H))_(t)-, wherein t is an integer from 1 to 6; and R¹¹ at eachoccurrence is independently H or C₁-C₆ alkyl.
 46. The compound accordingto claim 45, wherein X and X¹ are both hydrogen.
 47. The compoundaccording to claim 45, wherein R¹, R², R³ and R⁴ are independently H orhalogen.
 48. The compound according to claim 45, wherein R¹ is fluorineor chlorine.
 49. The compound according to claim 45, wherein R², R³, R⁵,and R⁶ are each hydrogen.
 50. The compound according to claim 45,wherein R¹¹ is H.
 51. The compound according to claim 45, wherein Z issulfur.
 52. The compound according to claim 45, wherein R³⁸ is NR³⁶R³⁹.53. The compound according to claim 45, wherein R⁴⁰ is H or C₁-C₁₀alkyl.
 54. The compound according to claim 1, represented by the formulaA-5.

and pharmaceutically acceptable salts thereof, wherein R⁷ is selectedfrom the group consisting of —C(O)NR⁴²R⁴³, —Y—(C₆-C₁₀aryl),—Y—(heteroaryl), —C(O)—(C₃-C₁₀ cycloalkyl), —C(O)—(heterocyclyl),—C(O)—(C₆-C₁₀ aryl) and —C(O)-heteroaryl), wherein the aforementioned R⁷groups are substituted with 1 to 5 independently selected R³⁸; R⁴ isselected from the group consisting of H and halogen; and T is selectedfrom the group consisting of cycloalkyl, heterocyclyl, aryl, heteroaryland arylalkyl, each of which is optionally substituted with 1 to 3independently selected R²⁰.
 55. The compound according to claim 54,wherein R⁷ is selected from the group consisting of C(O)NR⁴²R⁴³ and—Y—(heteroaryl), wherein —Y—(heteroaryl) is substituted with 1 to 5independently selected R³⁸.
 56. The compound according to claim 54,wherein R⁷ is C(O)NR⁴²R⁴³ substituted with 1 to 5 independently selectedR³⁸.
 57. The compound according to claim 54, wherein R⁴² and R⁴³ takentogether with the nitrogen to which they are attached form a C₅-C₉heterocyclyl ring, wherein said ring is substituted with 1 to 5independently selected R⁴⁴ substituents, with the proviso that R⁴² andR⁴³ are not both bonded to the nitrogen directly through and oxygen. 58.The compound according to claim 54, wherein R⁴ is halogen.
 59. Thecompound according to claim 1, represented by the formula A-6:

and pharmaceutically acceptable salts thereof, wherein R¹ is selectedfrom the group consisting of hydrogen, halo, C₁-C₆ alkyl, C₂-C₆ alkenylor C₂-C₆ alkynyl, wherein C₁-C₆ alkyl, C₂-C₆ alkenyl and C₂-C₆ alkynylare optionally substituted; R⁷ is selected from the group consisting ofC(═O)NR⁹R¹⁰, —C(═O)(C₆-C₁₀aryl), —C(═O)(heterocyclyl),—C(═O)(heteroaryl), —Y—(C₆-C₁₀aryl), —Y—(5 to 10 membered heterocyclyl),—Y—(heteroaryl), —SR^(6a), —S-aryl, —S—(heteroaryl), —S—C₁-C₆ alkyl,—SO—C₁-C₆ alkyl, —SO₂-C₁-C₆ alkyl, —NR⁹R¹⁰, —SO₂NR⁹R¹⁰CO₂R⁹,—C≡C—(CR⁴⁵R⁴⁵)_(n)—R⁴⁶ and —C(═NR⁴²)NR³⁷R⁴³, wherein n is an integerranging from 0 to 6 and wherein C₁-C₆ alkyl, aryl, heterocycle andheteroaryl are each independently substituted with 1 to 5 independentlyselected R³⁸; R⁹ and R¹⁰ are independently selected from the groupconsisting of C₁C₆ alkyl, —Y—(C₃-C₁₀cycloalkyl), —(C₁-C₆ heteroalkyl),—Y—(C₆-C₁₀aryl), —Y—(5 to 10 membered heterocyclyl),—Y—(C₆-C₁₀heteroaryl), —Y—O—Y¹—O—R¹¹, —Y¹—CO₂—R¹¹and —Y —O—R¹¹, whereinsaid C₁-C₆ alkyl, heteroalkyl, cycloalkyl, aryl, heterocycle, andheteroaryl are each substituted with one or more independently selectedR⁴⁴, or R⁹ and R¹⁰taken together with the nitrogen to which they areattached form a C₅-C₉ heterocyclyl ring or a heteroaryl ring, whereinsaid ring is substituted with 1 to 5 independently selected R⁴⁴; eachR²⁰ is independently selected from the group consisting of H, halo,—OR¹⁷ and —C(O)OR¹⁷; Y is a bond or is —(C(R¹¹)(H))_(t)—, wherein t isan integer from 1 to 6; Y¹ is —(C(R¹¹)(H)_(t)—; and R¹¹ at eachoccurrence is independently H or C₁-C₆ alkyl.
 60. The compound accordingto claim 59, wherein R⁷ is selected from the group consisting ofC(O)NR⁹R¹⁰ and —Y-(heteroaryl), wherein —Y—(heteroaryl) is substitutedwith 1 to 5 independently selected R³⁸.
 61. The compound according toclaim 59, wherein R⁹ and R¹⁰ taken together with the nitrogen to whichthey are attached form a C₅-C₉ heterocyclyl ring, wherein said ring issubstituted with 1 to 5 independently selected R⁴⁴ substituents.
 62. Thecompound according to claim 59, wherein R⁷ is —Y—(heteroaryl), whereinsaid —Y—(heteroaryl) is substituted with 1 to 5 independently selectedR³⁸.
 63. The compound according to claim 59, wherein R¹ is fluorine. 64.The compound according to claim 59, wherein R¹⁷ is selected from thegroup consisting of H and C₁-C₆ alkyl.
 65. The compound according toclaim 59, wherein R³⁷ is selected from the group consisting of H andC₁-C₆ alkyl.
 66. The compound according to claim 59, wherein each R²⁰ isindependently selected from the group consisting of H, halogen and—O—(C₁-C₆)alkyl.
 67. A pharmaceutical composition comprising thecompound according to claim 1 and a pharmaceutically acceptable carrier.68. The compound according to claim 23, wherein R⁷ is selected from thegroup consisting of

wherein the members of said group are optionally substituted by 1 to 3independently selected R³⁸.
 69. The compound according to claim 23,wherein R⁷ is selected from the group consisting of

wherein the members of said group are optionally substituted with 1 to 3independently selected R³⁸.
 70. The compound according to claim 31,wherein R⁷ is selected from the group consisting of

wherein the members of said group are optionally substituted by 1 to 3independently selected R³⁸.
 71. The compound according to claim 31,wherein R⁷ is selected from the group consisting of

wherein the members of said group are optionally substituted with 1 to 3independently selected R³⁸.
 72. The compound according to claim 31,wherein R⁷ is —Y—(heteroaryl), substituted with 1 to 5 independentlyselected R³⁸.
 73. The compound according to claim 31, wherein X and X¹are both H; R¹ is halogen, R⁷ is —Y—(heteroaryl), substituted with 1 to5 independently selected R³⁸; and R³⁸ is selected from the groupconsisting of —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,—(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, and —(CH₂)_(j)O(CH₂)_(i) ²NR³⁶R³⁹,wherein n is an integer ranging from 0 to 6, j is an integer rangingfrom 0 to 2, and is an integer ranging from 1 to
 6. 74. The compoundaccording to claim 1, wherein W is O; Z is S or O; X and X¹ are both H;R¹ is H or halogen; R², R³ and R⁴ are each H; D is CH; R is H orhalogen; E is E¹, wherein E¹ is selected from the group consisting of—C(O)NR⁴²R^(43, —SO) ₂NR⁴²R⁴³, C(═NR⁴²)NR³⁷R⁴³, —CO ₂R⁴²,—C(O)(heterocyclyl), —C(O)(heteroaryl), —Y—(C₆-C₁₀ aryl),—Y—(heteroaryl), —Y—(5 to 10 membered heterocyclic), —SR^(6a),—S(O)R^(6a), —SO₂R^(6a), wherein each of said E¹ are substituted with 1to 5 independently selected R³⁸; and R³⁸ is selected from the groupconsisting of —NR³⁶C(O)R³⁹, —NR³⁶R³⁹,—(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹,—S(O)_(j)(C₁-C₆alkyl),—(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,—(CH₂)_(n)NR³⁶R³⁹, wherein j is an integer ranging from 0 to 2, n is aninteger ranging from 0 to 6, i is an integer ranging from 1 to 6, the—(CH₂)_(i)- and —(CH₂)_(n)-moieties of the foregoing R³⁸ groupsoptionally include a carbon-carbon double or triple bond where n is aninteger between 2 and 6, and the alkyl, moieties of the foregoing R³⁸groups are optionally substituted by one or more substituentsindependently selected from the group consisting of halo, cyano, nitro,trifluoromethyl, azido, —OH, —C(O)R⁴⁰, —C(O)OR⁴⁰, —OC(O)R⁴⁰, —OC(O)OR⁴⁰,—NR³⁶C(O)R³⁹, —C(O)NR³⁶R³⁹, —(CH₂)_(n)NR³⁶R³⁹, C₁-C₆ alkyl, C₃-C₁₀cycloalkyl, —(CH₂)_(n)(C₆-C₁₀ aryl), —(CH₂)_(n)(5-10 memberedheterocyclyl), —(CH₂)_(n)O(CH₂)_(i) ²OR³⁷, and —(CH₂)_(n)OR³⁷, wherein nis an integer ranging from 0 to 6 and i² is an integer ranging from 2 to6.
 75. The compound according to claim 23, wherein X and X¹ are bothhydrogen; R¹ is fluorine; L is CH; R⁷ is Y-Heteroaryl substituted with 1to 5 independently selected R³⁸; and Z is sulfur.
 76. The compoundaccording to claim 31, wherein R¹ is fluorine; R⁷ is —Y-(heteroaryl)substituted with 1 to 5 independently selected R³⁸; R³⁸ is selected fromthe group consisting of —(CH₂)_(j)NR³⁹(CH₂)_(n)R³⁶,—(CH₂)_(j)NR³⁹(CH₂)_(i)NR³⁶R³⁹, and —(CH₂)_(j)O(CH₂)_(i)NR³⁶R³⁹, whereinn is an integer ranging from 0 to 6, is an integer ranging from 0 to 2,and i is an integer ranging from 1 to 6; R²⁰ is selected from the groupconsisting of H, halogen, OR¹⁷ and —C(O)0R¹⁷; X and X¹ are both H; andR¹⁷ is H or C₁-C₆alkyl.
 77. The compound according to claim 1, selectedfrom the group consisting of1-(4-(2-(N-methoxy-N-methylcarbamoyl)thieno[3,2-b]pyridin-7yloxy)-3-fluorophenyl)-3-(2-phenylacetyl)thiourea,7-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-carboxylicacid (2-diisopropylamino-ethyl)-amide, formate salt,(R)-N-(3-Fluoro-4-(2-(3-Hydroxypyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylearbamothioyl)-2-phenylacetamide,(S)-N-(3-Fluoro-4-(2-(3-hydroxypyrrolidine-l-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide,7-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-carboxylicacid (2-dimethylamino-ethyl)-amide, formate salt,7-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-carboxylicacid bis -(2-methoxy-ethyl)-amide,7-[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-carboxylicacid (2-cyano-ethyl)-phenyl-amide,N-(3-Fluoro-4-(2-(4-(methylsulfonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide,1-(3-Fluoro-4-(2-(3-morpholinoprop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea,2-((4-7-(2-Fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)methylamino)ethanol,N-(3-Fluoro-4-(2-(3-((2-methoxyethylamino)methyl)phenyl)thieno[3,2]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide,1-(3-Fluoro-4-(2-(2-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea,1-(3-Fluoro-4-(2-(3-((2-morpholinoethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea,N-(3-Fluoro-4-(2-(4((2-(methylamino)ethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide1-(3-Fluoro-4-(2(3-((2-methoxyethylamino)methyl)phenyl)thieno[3,2-b]pyridin-7 -yloxy)phenyl)-3-(2-phenyl acetyl)thiourea,1-(3-Fluoro-4-(2-(3-(2-(methylamino)ethylamino)methyl)phenypthieno[3,2-b]pyridin- 7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea,1-(3-Fluoro-4-(2-(4-(((tetrahydrofuran-2-yl)methylamino)methyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-(2-phenylacetyl)thiourea,7[2-Fluoro-4-(3-phenylacetyl-thioureido)-phenoxy]-thieno[3,2-b]pyridine-2-sulfonic acid amide,(R)-N-(4-(2-(3-(Dimethylamino)pyrrolidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)-3- fluorophenylcarbamothioyl)-2-phenylacetamide,N-(3-Fluoro-4-(2-(4-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide,N-(3-Fluoro-4-(2-(2-hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide,N-(3-Fluoro-4-(2-(3-hydroxyphenypthieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide,N-(4-(2-(4-(4-Aminobutoxy)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbam othioyl)-2-phenylacetamidedi-hydrochloride,N-(3-Fluoro-4-(2-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyI)-2-(2-methoxyphenyl)acetamide,N-(4-(2-(4-Hydroxyphenyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-phenylacetamide,N-(3-Fluoro-4-(2-(3-hydroxyazetidine-1-carbonyl)thieno[3,2-b]pyridin-7-yloxy)phenylcarbamothioyl)-2-(2-methoxyphenyl)acetamide,andN-(4-(2-(4-(Dimethylamino)phenyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide.